MOTS-c - a peptide that supports mitochondria

Description of potential effects of MOTS-c substance based on literature. (This is not a product description, disclaimer at the bottom of the page)

 

MOTS-c (mitochondrial ORF type C rRNA 12S)

Mitochondrial ORF type 12S rRNA type C (MOTS-c) is a newly characterized peptide of mitochondrial origin. It consists of 16 amino acids and is encoded in the 12S rRNA region of the mitochondrial genome [1]. Under normal physiological conditions, MOTS-c is mainly found in mitochondria, but when cells experience metabolic stress, the peptide translocates to the cell nucleus, where it modulates the expression of nuclear genes involved in maintaining cellular homeostasis [1]. 

Although MOTS-c is encoded by mitochondrial DNA, it is synthesized in the cytoplasm rather than in mitochondria [1]. This is because the mitochondrial genetic code is different from that of the cytosol, allowing the export of the polyadenylated MOTS-c transcript into the cytoplasm for translation. The amino acid sequence of MOTS-c, especially the first 11 residues, shows a high degree of conservatism in many species [1]. 

MOTS-c was originally discovered through genetic and pharmacological screening methods aimed at identifying regulators of metabolic processes. Later studies showed that MOTS-c plays a role in the regulation of glucose metabolism and insulin sensitivity, mainly through activation of AMP-activated protein kinase (AMPK)-dependent signaling pathways [1]. In addition, blood levels of MOTS-c have been found to vary with age, metabolic status and population characteristics, suggesting a broader role in regulating systemic metabolism.

Role of MOTS-c in metabolism and protection against diabetes and metabolic stress

Several scientific studies have described the potential role of MOTS-c in energy metabolism and metabolic stress. In multiple animal and cellular models, MOTS-c consistently improved glucose metabolism, insulin sensitivity and lipid metabolism while reducing weight gain and tissue damage. These effects extend beyond metabolic control and include protection of the heart, liver, pancreas, nerves and immune balance, particularly in diabetic and aging-related conditions. Mechanistically, MOTS-c works through central pathways of energy sensing and stress response, enabling cells and organs to adapt more effectively to excess nutrients, oxidative stress and inflammation. The results of these studies indicate that MOTS-c is a broadly acting regulator of metabolic immunity with exercise-like and tissue-protective properties.

In a research study, Lee et al (2015) identified MOTS-c, a small peptide produced in mitochondria, the energy centers of cells [2]. MOTS-c is 16 amino acids long and is encoded by the MOTS-c gene ( ) in mitochondrial RNA. The study analyzed MOTS-c in muscle cells and mice exposed to aging stress and a high-fat diet. In muscle cells, MOTS-c slowed down specific metabolic pathways and activated AMPK, an energy-sensing switch that helps cells use glucose more efficiently. In mice, MOTS-c prevented insulin resistance associated with aging and a high-fat diet. The treated animals gained less weight and accumulated less body fat. They exhibited better blood sugar control and greater flexibility in the body's energy use. These results show that MOTS-c helps maintain a healthy metabolism by improving energy regulation in muscles.

In addition, Yin et al (2022) evaluated MOTS-c in gestational diabetes, a condition in which blood sugar levels rise during pregnancy [3]. The researchers used pregnant mice fed a high-fat diet combined with mild chemical stress to model the disease. MOTS-c was administered daily throughout pregnancy. The treatment lowered fasting blood sugar levels and reduced excess insulin in the bloodstream. It also improved insulin sensitivity. In muscle cell studies, MOTS-c increased glucose uptake, allowing sugar to enter the cells more easily. MOTS-c protected insulin-producing pancreatic cells from damage and helped maintain insulin secretion. Pregnancy outcomes also improved. Treated animals showed less excessive fetal growth and lower neonatal mortality rates. These results show that MOTS-c supports both maternal metabolism and healthier pregnancy outcomes in gestational diabetes.

In addition, Kim et al (2018) examined how MOTS-c functions inside cells during metabolic stress [4]. When glucose or nutrients were limited, MOTS-c moved from the mitochondria to the cell nucleus, where gene activity is controlled. This movement depended on AMPK activation. In the nucleus, MOTS-c regulated genes involved in metabolism, stress adaptation and antioxidant protection. It interacted with NRF2, a key regulator of cellular defense against oxidative damage. MOTS-c helped activate protective gene programs that allow cells to cope with metabolic and oxidative stress. The findings show that MOTS-c enables direct communication between mitochondria and the cell nucleus, helping cells quickly adapt to energy deficiencies.

In addition, Tang et al (2023) studied MOTS-c in a rat model of type 2 diabetes caused by a high-fat diet and low-dose streptozotocin [5]. Rats received MOTS-c at a dose of 0.5 mg per kg body weight per day by injection for eight weeks. Effects were compared with aerobic exercise and with a combination of MOTS-c and exercise. MOTS-c improved cardiac structure and function. Microscopic analysis showed less damage to myocardial fibers and mitochondria. MOTS-c also improved blood sugar and fat metabolism. It enhanced the heart's antioxidant protection by increasing levels of superoxide dismutase, catalase and glutathione. At the same time, it reduced levels of malondialdehyde, a marker of oxidative damage. MOTS-c activated the AMPK and NRF2 signaling pathways. The strongest protective effect was observed when MOTS-c was combined with exercise. These results suggest that MOTS-c mimics the key benefits of exercise and may help protect the heart in diabetes, especially when physical activity is limited.

In another study, Chen et al (2025) investigated MOTS-c for liver scarring associated with type 2 diabetes, also known as liver fibrosis [6]. The condition develops when long-term diabetes damages liver tissue. The researchers used rats with diabetes that already had liver fibrosis and compared three approaches: MOTS-c treatment, aerobic exercise and a combination of both. The rats with diabetes showed poor liver function and significant collagen accumulation, indicating fibrosis. MOTS-c improved liver structure and reduced scarring. Exercise provided similar benefits, while the combination of the two treatments produced the strongest improvement. Liver function also improved in all treatment groups. At the molecular level, MOTS-c activated the Keap1-Nrf2 pathway, which enhances antioxidant protection of the liver. This reduced the amount of harmful reactive oxygen species in liver cells. At the same time, MOTS-c inhibited the TGF-β1-Smad2/3 pathway, a major contributor to scar formation. Cellular studies confirmed these effects. Increasing MOTS-c elevated the activity of antioxidant genes and decreased the activity of fibrosis-related genes, while blocking MOTS-c reversed these benefits. These results show that MOTS-c reduces diabetic liver fibrosis by enhancing antioxidant protection and reducing scar formation, closely mimicking the effects of aerobic exercise.

In addition, Pham et al (2025) investigated whether MOTS-c could improve energy production in the hearts of rats with type 2 diabetes [7]. Diabetes was induced with a high-fat diet combined with a low dose of streptozotocin. The rats then received daily injections of MOTS-c at a dose of 15 mg per kg of body weight for three weeks. The untreated diabetic rats developed high blood sugar levels, poor glycemic control and myocardial enlargement. The mitochondria of their hearts showed poor oxygen utilization during energy production, indicating reduced efficiency. MOTS-c treatment lowered fasting blood glucose levels and reduced cardiac enlargement. At the cellular level, MOTS-c improved mitochondrial respiration and oxygen utilization. It also reduced ATP breakdown during low-oxygen stress, helping to conserve energy stores. Reactive oxygen species increased slightly, but remained within a healthy adaptive range. These findings show that MOTS-c restores mitochondrial efficiency and improves cardiac energy metabolism in type 2 diabetes.

In addition, Kim et al (2019) investigated how MOTS-c affects metabolic markers in blood in mice with diet-induced obesity [8]. Obese mice were treated with MOTS-c injections, and plasma metabolites were analyzed using an objective screening method. MOTS-c reduced several metabolic pathways that are typically elevated in obesity and diabetes, including sphingolipid metabolism , monoacylglycerol metabolism and dicarboxylate metabolism. These pathways are linked to fat accumulation and metabolic stress. In addition to these changes, MOTS-c increased fatty acid breakdown, reduced fat accumulation and improved insulin sensitivity. Blood sugar management was also improved. These results show that MOTS-c transforms circulating metabolites in a way that promotes better energy utilization and insulin response, helping to protect against the metabolic damage associated with obesity.

In addition, Yang et al (2021) examined how MOTS-c and exercise work together to improve glucose metabolism [9]. The study focused on the AMPK-PGC-1α pathway, which controls energy production in muscle and mitochondrial growth. In experiments on muscle cells, blocking AMPK reduced both PGC-1α and MOTS-c levels. Decreasing PGC-1α levels also decreased MOTS-c expression. In contrast, increasing PGC-1α levels or adding recombinant MOTS-c increased endogenous MOTS-c levels, demonstrating a positive feedback loop. In obese mice, MOTS-c levels in muscle and blood were reduced. Treadmill exercise restored MOTS-c levels and increased PGC-1α, GLUT4 and AMPK signaling. These changes led to better insulin sensitivity and improved glucose metabolism. The findings show that MOTS-c and exercise mutually reinforce each other through a common energy regulation pathway, which argues for their combined or stand-alone use to improve insulin resistance and metabolic health.

In another study, Wu et al (2025) investigated whether MOTS-c can protect the heart in cardiomyopathy associated with type 1 diabetes, a condition in which long-term diabetes damages cardiac structure and function [10]. Type 1 diabetes was induced in mice using streptozotocin. After the onset of the disease, the mice received continuous administration of MOTS-c under the skin via osmotic pumps for 12 weeks. The diabetic mice developed enlarged cardiac chambers, impaired pumping ability and abnormal cardiac remodeling. MOTS-c treatment improved overall cardiac function and restored ventricular performance. Cardiac structure was preserved and tissue damage was reduced. Microscopic analysis showed less scarring of the heart and better tissue integrity. At the molecular level, diabetes inhibited AMPK signaling and increased inflammation in heart tissue. MOTS-c reactivated AMPK and lowered inflammatory markers. These findings show that long-term treatment with MOTS-c protects the diabetic heart by improving energy balance and reducing inflammation.

In addition, Kong et al (2021) investigated whether MOTS-c can protect insulin-producing pancreatic cells in autoimmune diabetes [11]. The study used non-obese diabetic mice, a common model of type 1 diabetes caused by immune attack on the pancreas. MOTS-c treatment delayed or prevented the rise in blood sugar levels. Examination of pancreatic tissue showed significantly fewer immune cells attacking insulin-producing islets. This indicated a strong protection against autoimmune damage. In transfer experiments, immune T cells taken from MOTS-c-treated mice caused less diabetes when transferred to immune-deficient mice. This showed that MOTS-c directly altered T-cell behavior. Further analysis showed that MOTS-c altered T-cell activation and metabolism by regulating the TCR-mTORC1 pathway, which controls energy consumption and immune cell activation. MOTS-c helped T cells cope with metabolic stress and reduced harmful overactivity. Blood samples taken from people with type 1 diabetes showed lower levels of MOTS-c than in healthy people. In laboratory tests, MOTS-c reduced the activation of human T cells under stress. These findings indicate that MOTS-c protects pancreatic cells by mitigating harmful immune responses, and may have a role in autoimmune diabetes.

In addition, Fu et al (2024) investigated whether MOTS-c can reduce cardiac damage caused by inflammation and oxidative stress associated with diabetes [12]. Diabetes was induced in rats using a high-sugar and high-fat diet, followed by low doses of streptozotocin. The rats were then given MOTS-c at a dose of 0.5 mg per kg body weight per day by injection for eight weeks. The diabetic rats showed high levels of harmful oxygen byproducts, increased levels of TXNIP and activation of the NLRP3 inflamasome, a major inflammation inducer. MOTS-c treatment reduced oxidative stress and lowered the levels of TXNIP and NLRP3 in cardiac tissue. Cardiac inflammation decreased and tissue structure improved compared to untreated diabetic rats. These results show that MOTS-c protects the diabetic heart by turning off a key inflammatory pathway caused by oxidative stress.

Interestingly, Lu et al (2019) studied MOTS-c in a model of menopause-related metabolic decline caused by estrogen loss [13]. Female mice underwent ovarian resection, which led to weight gain, increased body fat, inflammation and insulin resistance. MOTS-c treatment prevented excessive weight gain and preserved insulin sensitivity. It increased the activity of brown adipose tissue, which burns energy and generates heat. This resulted in an increase in overall energy consumption. In white adipose tissue, MOTS-c reduced fat accumulation and decreased immune cell infiltration, leading to reduced inflammation. Fatty acid levels in the blood dropped, and fat deposition in the liver was reduced. At the molecular level, MOTS-c activated AMPK, a key regulator of energy and fat metabolism. Blocking AMPK reduced the benefits of MOTS-c, confirming its key role. These findings show that MOTS-c helps maintain healthy adipose tissue function and protects against metabolic problems associated with menopause.

In addition, Li et al (2022) investigated how MOTS-c affects diabetic heart disease and whether its benefits are similar to those of aerobic exercise [14]. Using rats with type 2 diabetes caused by a high-fat, high-sugar diet and low-dose streptozotocin, the researchers subjected the animals to MOTS-c or aerobic exercise. They then assessed cardiac structure, heart function and gene expression. As expected, the diabetic rats showed impaired cardiac function and abnormal cardiac remodeling of the „ ” type. However, both MOTS-c treatment and exercise significantly improved the structure of the heart and restored its pumping ability. In particular, thinning of the heart's ventricular walls, ventricular enlargement and poor contractility were markedly reduced. In addition, gene analysis showed that MOTS-c reproduced many effects similar to those achieved by exercise. These included reduced inflammation, less cardiac cell death, increased formation of new blood vessels, and improved movement and growth of endothelial cells lining blood vessels. Importantly, MOTS-c activated the NRG1-ErbB4 signaling pathway, a key system supporting cardiac cell survival, repair and blood vessel health. Overall, these results show that MOTS-c restores cardiac function in diabetes by activating the same protective pathways that are triggered by aerobic exercise.

Figure 1. Metabolic and protective role of MOTS-c in diabetes and metabolic stress (based on animal studies)

Similarly, Wang et al (2023) investigated whether MOTS-c could repair cardiac damage and improve cardiac performance in rats with diabetes [15]. Diabetes was induced with a high-sugar and high-fat diet combined with streptozotocin, which led to mitochondrial damage, increased cell death and poor cardiac contractility and diastolic performance. The rats were treated with MOTS-c for eight weeks. After treatment, cardiac mitochondria showed improved structure and integrity. At the same time, both systolic and diastolic function of the heart improved significantly. Gene sequencing showed that MOTS-c regulated 47 disease-related genes linked to diabetes-induced heart damage. These changes affected processes such as inflammation control, blood vessel growth, fat metabolism and cell survival. Mechanistically, MOTS-c reduced cardiac cell death by downregulating CCN1 and blocking the ERK1/2 signaling pathway, which in turn reduced levels of EGR1, the gene responsible for damaging remodeling. Taken together, these results show that MOTS-c repairs cardiac tissue and preserves cardiac function by reducing cell death and improving mitochondrial health in diabetes (Wang et al., 2023).

In addition to the heart, Kong et al (2025) investigated whether MOTS-c can prevent the age-related decline in the number of pancreatic cells that produce insulin, a key factor in the development of diabetes [16]. The study analyzed old mice, insulin-resistant mice and models of autoimmune diabetes. In all models, aging and disease were associated with a sharp decline in MOTS-c levels in pancreatic islets. When MOTS-c was administered to old islets, markers of cellular aging decreased and gene activity shifted toward healthier metabolic patterns. In live animals, MOTS-c improved insulin secretion and glucose tolerance in both insulin-resistant and autoimmune diabetes models. Importantly, MOTS-c consistently reduced markers of aging and preserved the structure and function of insulin-producing cells. In human samples, people with type 2 diabetes showed significantly lower levels of MOTS-c in their blood than healthy individuals. In conclusion, these results show that MOTS-c helps delay the progression of diabetes by preventing premature aging of pancreatic cells and maintaining insulin function.

In another study, Xu et al (2024) tested whether MOTS-c could treat painful diabetic neuropathy, which is a common and debilitating complication of diabetes [17]. In mice with streptozotocin-induced diabetes, the level of natural MOTS-c fell sharply in both the blood and spinal cord. As a result, the mice developed high blood sugar levels, weight loss and increased sensitivity to pain, including pain caused by light touch and heat. After MOTS-c treatment, blood sugar levels improved, body weight stabilized, and pain sensitivity decreased significantly. However, when AMPK signaling was blocked, these benefits disappeared, confirming that AMPK activation was essential. At the molecular level, MOTS-c increased AMPK and PGC-1α activity in the spinal cord. This restored mitochondrial production, reduced the overactivity of immune cells in nerve tissue and lowered inflammatory signals. As a result, nerve inflammation and pain signaling decreased. Overall, this study shows that MOTS-c reduces diabetic nerve pain by restoring mitochondrial health, alleviating inflammation and improving energy signaling, suggesting a disease-modifying approach rather than just alleviating pain.

MOTS-c in muscle mass preservation, tissue repair and exercise adaptation

Scientific studies have demonstrated MOTS-c's potential role in preserving muscle mass, promoting tissue repair and improving physiological adaptation to stress and exercise. Evidence from human, cell and animal studies indicates that MOTS-c reduces muscle atrophy, improves muscle quality and maintains muscle strength during obesity, immobilization, aging and metabolic stress. Beyond muscle, MOTS-c contributes to cell membrane repair, bone integrity, blood vessel health and cardiac adaptation by coordinating energy pathways, survival and stress responses.

Kumagai et al (2021) examined how MOTS-c affects muscle loss associated with obesity, insulin resistance and metabolic stress [18]. The researchers combined human data, cellular experiments and animal studies. In humans, higher blood levels of MOTS-c were associated with lower levels of myostatin, a protein that slows muscle growth and promotes muscle atrophy. In muscle cells exposed to fatty acids, MOTS-c prevented shrinkage and preserved muscle structure. Similarly, in diet-induced obese mice, MOTS-c reduced blood myostatin levels and improved markers associated with muscle preservation. At the molecular level, MOTS-c activated a signaling chain including CK2, PTEN, mTORC2 and AKT. This resulted in inhibition of FOXO1, a gene regulator responsible for muscle atrophy. Taken together, these results indicate that MOTS-c protects muscle by blocking myostatin signaling and restricting pathways that promote muscle breakdown under metabolic stress.

Based on these studies, Kumagai et al (2024) identified a direct molecular target through which MOTS-c protects muscle [19]. Using biochemical assays, the researchers showed that MOTS-c physically binds to and activates CK2, an enzyme important for cell survival and metabolism. In mice, systemic treatment with MOTS-c prevented muscle atrophy and increased glucose uptake into muscle tissue. However, when CK2 activity was blocked, these benefits were largely lost, confirming that CK2 activation is essential for MOTS-c to work. Interestingly, MOTS-c activated CK2 in skeletal muscle, but inhibited CK2 activity in adipose tissue, showing tissue-specific regulation . Moreover, a naturally occurring variant of human MOTS-c, known as K14Q, did not bind to or activate CK2 and did not protect against muscle loss or metabolic disorders. Genetic data showed that men carrying this variant had a higher risk of muscle loss and type 2 diabetes, especially with age and low physical activity. These findings identify CK2 as a key mediator of MOTS-c's muscle and metabolic protection effects.

In addition to preserving muscle mass, Jia et al (2024) found that MOTS-c plays a direct role in repairing damaged cell membranes, a process crucial to muscle health and regeneration [20]. In human studies, higher blood levels of MOTS-c were associated with higher mitochondrial content and higher expression of TRIM72, a protein that repairs damaged muscle cell membranes. Moderate exercise increased the release of MOTS-c and promoted its movement to damaged cell membrane sites, where it interacted with TRIM72. In cellular studies, MOTS-c reduced physical stress-induced cell membrane damage, but this protection disappeared when TRIM72 was blocked, indicating a TRIM72-dependent repair mechanism. Importantly, this effect did not require AMPK activation. MOTS-c bound directly to the tail end of TRIM72 and helped to move it quickly to damage sites. At the same time, MOTS-c also improved membrane repair even in animals lacking TRIM72 by binding to a membrane lipid called PtdIns(4,5)P₂, which promotes vesicle fusion. In cardiac injury models, MOTS-c preserved membrane integrity and improved cardiac function. Overall, these results show that MOTS-c promotes membrane repair through both protein- and lipid-based mechanisms.

In addition, Leciejewska et al (2025) examined how MOTS-c affects different types of muscle fibers [21]. The study compared oxidative muscle cells, which rely more on endurance metabolism, with glycolytic muscle cells, which rely more on rapid energy consumption. MOTS-c was tested at physiologically relevant concentrations ranging from 10 to 100 nM. In oxidative muscle cells, MOTS-c increased cell survival, rapidly activated ERK signaling within minutes, and promoted muscle differentiation by increasing key muscle-forming factors. The cells also processed fat more efficiently and accumulated less lipids under stress conditions. In contrast, glycolytic muscle cells showed no improvement in survival or differentiation after MOTS-c treatment, and instead accumulated more lipids. Interestingly, MOTS-c reduced cell proliferation in both types of muscle, suggesting a shared role in controlling cell growth. These findings show that MOTS-c acts in a fiber type-specific manner and may preferentially promote oxidative muscle health, which is important for endurance, metabolic stability and resistance to muscle loss.

In addition, Lu et al (2019) investigated whether MOTS-c helps the body adapt to cold by improving heat production in adipose tissue [22]. Cold exposure reduced the natural level of MOTS-c in the blood of mice with increased glucose sensitivity ( ), suggesting that this peptide is depleted during stress. The researchers therefore administered MOTS-c to see if it could improve cold tolerance. As expected, the treated animals tolerated cold exposure better and showed a smaller drop in body temperature. In addition, fat leakage into the liver decreased, indicating improved metabolic stability. At the tissue level, MOTS-c increased the activity of heat-producing genes in brown adipose tissue and promoted the conversion of white adipose tissue into a more thermally active form, a process known as browning. In addition, MOTS-c activated ERK signaling, and blocking this pathway prevented the increase in thermogenic genes. Taken together, these results indicate that MOTS-c enhances cold adaptation by increasing heat production in adipose tissue via ERK-dependent signaling.

In a separate study, Li et al (2025) examined whether MOTS-c protects cartilage in osteoarthritis, a joint disease caused by inflammation, mechanical stress and metabolic imbalance [23]. In cellular and mouse models, MOTS-c improved mitochondrial function and reduced oxidative stress in cartilage cells. As a result, inflammatory cell death known as pyroptosis was strongly inhibited. Mechanistically, MOTS-c activated Nrf2, which then blocked TXNIP and prevented the activation of the NLRP3 inflamasome, a key driver of inflammation and cartilage damage. Functionally, MOTS-c reduced inflammatory cytokines, decreased cartilage-degrading enzymes and restored healthy extracellular matrix components. In mice with osteoarthritis, MOTS-c slowed cartilage degeneration and preserved joint structure. These findings show that MOTS-c protects joints by improving mitochondrial health, reducing inflammation and preventing cartilage breakdown.

Figure 2. health potential of MOTS-c (based on animal studies)

Interestingly, Yuan et al (2023) investigated whether MOTS-c exerts beneficial effects on the heart, similar to the effects of exercise, through activation of adaptive growth pathways [24]. Rats received MOTS-c, performed aerobic exercise or both, and then the structure and function of their hearts were carefully measured. Both interventions increased heart weight in a healthy way, reflecting physiological rather than detrimental enlargement. Myocardial fibers became thicker and more organized. At the same time, heart function improved, with the heart starting to beat slower, relax better and contract more strongly. Importantly, intracardiac pressure at rest did not increase, confirming that the changes were beneficial. At the molecular level, MOTS-c and exercise activated the same signaling pathway involving NRG1, ErbB4 and reduced C/EBPβ expression. This pattern supports healthy cardiac growth and improved cardiac performance. Overall, these results show that MOTS-c closely mimics aerobic exercise, activating pathways that promote robust and adaptive cardiac function.

In addition, Kumagai et al (2024) investigated whether MOTS-c can prevent muscle loss caused by immobilization, which mimics the inactivity observed in trauma, aging and chronic diseases [25]. Male mice were immobilized for eight days and received daily injections of MOTS-c at a dose of 15 mg per kg of body weight. Immobilization alone resulted in approximately 15% of muscle loss. In contrast, mice treated with MOTS-c lost only about 5% of muscle mass. At the molecular level, MOTS-c restored key growth-preserving signals, including AKT and FOXO proteins, which are normally inhibited during muscle atrophy. In addition, the number of inflammatory markers in the blood was significantly reduced. Gene analysis showed that MOTS-c reduces fat formation pathways in muscle, which confirmed a reduction in fat deposition in muscle tissue. These results show that MOTS-c protects against muscle atrophy caused by physical inactivity by reducing inflammation, limiting fat infiltration and restoring signals responsible for preserving muscle mass.

In addition, Wei et al (2020) investigated whether MOTS-c can reduce vascular calcification and protect the heart from secondary damage [26]. In this study, rats developed blood vessel calcification after treatment with vitamin D₃ and nicotine, which also leads to harmful cardiac remodeling. The rats were then given MOTS-c at a dose of 5 mg per kg body weight per day by injection for four weeks. As a result, vascular calcification was significantly reduced. At the molecular level, MOTS-c increased the activation of AMPK, a key pathway that promotes metabolic balance and reduces inflammation. At the same time, the expression of angiotensin II type 1 receptor and endothelin B receptor, known to cause vasoconstriction, inflammation and tissue remodeling, was reduced. Importantly, MOTS-c also improved cardiac structure, reducing secondary remodeling caused by vascular calcification. Blood pressure, heart rate and body weight remained stable, with no adverse effects. Overall, these results show that MOTS-c protects blood vessels and the heart by activating AMPK and reducing harmful vascular signaling.

Similarly, Wu et al (2023) investigated whether MOTS-c can protect the heart during sepsis, a severe inflammatory condition that often leads to heart failure [27]. Using a model of septic cardiomyopathy caused by a bacterial toxin, the researchers found that MOTS-c strongly reduced cardiac inflammation. Levels of inflammatory markers such as IL-1β, IL-4, IL-6 and TNF-α were reduced, and blood markers indicative of cardiac injury, including CK-MB and troponin T, were also reduced . In addition, MOTS-c improved mitochondrial function, reduced oxidative stress and prevented cardiac cell death. Mechanistically, MOTS-c activated protective signaling pathways, including AMPK, AKT and ERK, while inhibiting inflammatory pathways such as JNK and STAT3. Interestingly, when AMPK was blocked, all protective effects of MOTS-c disappeared. This confirmed that AMPK activation is essential for MOTS-c to function. Taken together, these results show that MOTS-c protects the heart in sepsis by mitigating inflammation, restoring energy balance and preventing cell loss.

Aside from cardiometabolic diseases, Ran et al. (2021) investigated whether MOTS-c can improve gene therapy in Duchenne muscular dystrophy, a severe disease causing muscle wasting [28]. The study used dystrophic mice and muscle cells treated with exon-skipping drugs known as PMOs. The mice received MOTS-c at a dose of 500 micrograms per dose along with PMO therapy at 12.5 mg per kg per week for three weeks, followed by monthly doses for three months. MOTS-c increased sugar breakdown and energy production in muscle cells, creating conditions that improved PMO uptake. As a result, there was a significant improvement in dystrophin restoration in the muscles. In the diaphragm, the level of dystrophin increased up to 25-fold compared to PMO therapy alone. Muscle function improved, and no toxicity was observed. These results show that MOTS-c acts as a metabolic enhancer that increases drug delivery and efficacy in energy-deficient muscles, supporting its use as an adjunctive therapy in muscular dystrophy.

In another study, Hyatt (2022) examined how MOTS-c responds to prolonged training and whether a single dose can improve physical performance [29]. In mice that were allowed to run voluntarily for four to eight weeks, MOTS-c levels increased 1.5 to 5 times in many leg muscles. This increase persisted up to six weeks after the training, showing long-term effects. The increase in MOTS-c closely matched the increase in mitochondrial DNA, indicating that exercise-induced mitochondrial growth increases the MOTS-c pool. In separate experiments, a single injection of MOTS-c at a dose of 15 mg per kg improved physical performance during intense exercise in untrained mice. Running time increased by 12%, and running distance increased by 15%. In addition, MOTS-c moved to the nucleus accumbens of slow contractile muscle fibers after running downhill, suggesting its role in stress adaptation. Taken together, these results indicate that MOTS-c is an exercise-responsive signal that increases endurance, promotes mitochondrial health, and may help maintain metabolic resilience during periods of reduced activity.

In addition, Yan et al (2019) investigated whether MOTS-c can protect bones from damage caused by wear particles, which often lead to bone loss around joint implants [30]. In a mouse model of arthritis ( ), fine plastic particles induced severe inflammation and bone erosion. However, after MOTS-c administration, bone mass loss was significantly reduced and local inflammation subsided. At the cellular level, MOTS-c altered bone signaling in a protective direction by increasing the balance of osteoprotegerin versus RANKL, which helps block excessive bone breakdown. At the same time, MOTS-c inhibited inflammatory signaling in bone immune cells by reducing NF-κB and STAT1 activation. Importantly, when oxidative stress was artificially increased or AMPK and PGC-1α signaling was blocked, the protective effects of MOTS-c disappeared. Taken together, these results demonstrate that MOTS-c reduces particle-induced bone destruction by attenuating inflammation and restoring healthy bone cell communication through an AMPK-dependent pathway.

Similarly, Ming et al (2016) investigated whether MOTS-c could prevent bone mass loss caused by estrogen deficiency, a major contributor to postmenopausal osteoporosis [31]. Female mice had their ovaries excised and were then given daily injections of MOTS-c at a dose of 5 mg per kg of body weight for 12 weeks. As a result, bone volume and structure were preserved, as demonstrated by detailed imaging of bone architecture. In cellular studies, MOTS-c strongly reduced the formation of osteoclasts, the cells responsible for bone breakdown. At the molecular level, MOTS-c increased the activation of AMPK, a pathway known to promote bone balance and energy regulation. When AMPK was blocked, MOTS-c's protective effect on bone was partially lost. These results indicate that MOTS-c protects against hormone-related bone mass loss by reducing bone resorption through AMPK activation.

In addition, Sidorenko et al (2025) investigated whether MOTS-c can prevent muscle loss caused by mechanical strain relief, a condition resembling immobilization, prolonged bed rest, aging and microgravity [32]. Male rats were subjected to a seven-day hind limb suspension and given daily MOTS-c injections during this period. As expected, the untreated animals showed severe muscle fatigue, loss of slow-twitch muscle fibers and general muscle shrinkage. In contrast, rats treated with MOTS-c retained muscle strength and showed significantly less fatigue. Muscle analysis confirmed the preservation of slow contractile fibers and a reduction in muscle atrophy. At the molecular level, MOTS-c maintained key protein-building signals, including phosphorylation of Akt and GSK3β, and preserved levels of ribosomal RNA needed for protein production. It also inhibited genes responsible for muscle atrophy, such as MuRF1 and Atrogin-1, and preserved markers of mitochondrial formation and AMPK-related signaling. Taken together, these results indicate that MOTS-c preserves muscle metabolism, structure and strength during periods of inactivity, supporting its potential role in preventing muscle loss during immobilization and inactivity.

In another study, Yuan et al (2021) examined the effects of MOTS-c on cardiac performance during aerobic training [33]. Aerobic exercise naturally increases MOTS-c levels, and MOTS-c itself is known to improve physical performance. Therefore, the researchers tested whether adding MOTS-c during training could further improve cardiac performance. Rats were given MOTS-c while performing aerobic exercise, and cardiac performance was measured using detailed pressure and volume analysis. As a result, the MOTS-c-treated rats showed an improvement in the mechanical efficiency of the heart muscle, meaning that the heart converted energy into pumping work more efficiently. In addition, systolic function improved, indicating stronger heart contractions. Diastolic function also improved, although to a lesser extent. Taken together, these results indicate that MOTS-c enhances the benefits of aerobic training for the heart and may act as a fitness-related mitochondrial signal that improves exercise-induced cardiac adaptation.

In a separate study, Che et al (2019) examined whether MOTS-c improves bone health by increasing collagen production in bone-forming cells [34]. Since type I collagen is the main structural protein of bone, its production is crucial for bone strength. Human osteoblast cells were treated with MOTS-c at different doses and at different times. MOTS-c increased cell viability in a time- and dose-dependent manner, with the strongest effects observed at a concentration of 1.0 μM after 24 hours and 0.5 μM after 48 hours. In addition, MOTS-c increased the expression of type I collagen genes and proteins, including COL1A1 and COL1A2. At the level of signaling, MOTS-c activated the TGF-β/SMAD pathway, which controls bone formation. When key components of the pathway were inhibited, MOTS-c's action to increase collagen production was diminished. These results show that MOTS-c enhances bone matrix formation by activating the central bone-building pathway, confirming its potential role in the treatment of osteoporosis.

Meanwhile, Domin et al (2023) investigated whether blood levels of MOTS-c are associated with physical performance in healthy adults [35]. Participants performed jump tests to measure muscle strength and power, and an exercise test to assess aerobic capacity. Higher MOTS-c levels at rest were clearly associated with greater muscle strength, greater jumping power and greater muscle mass, especially in the lower body. However, MOTS-c levels showed no relationship with maximal oxygen uptake, a measure of endurance capacity. These results suggest that MOTS-c is more closely related to muscle strength and power than to aerobic capacity. As a result, MOTS-c may serve as a biomarker of muscle strength rather than overall endurance capacity.

In another study, Hu and Chen (2018) investigated whether MOTS-c promotes bone formation by increasing the differentiation of bone marrow stem cells into bone-forming cells [36]. After MOTS- u c administration, the stem cells showed greater mineral accumulation, confirming stronger bone formation activity. This was confirmed by increased staining of calcium deposits and alkaline phosphatase, which are markers of bone formation. In addition, MOTS-c increased the expression of key bone-related genes, including Runx2, osteocalcin and ALP. At the molecular level, MOTS-c activated the TGF-β/Smad signaling pathway. When TGF-β1 was silenced, MOTS-c's bone-forming-promoting effects were largely lost. These findings demonstrate that MOTS-c promotes bone regeneration by directing stem cells to bone formation pathways, highlighting its potential in osteoporosis treatment and bone repair strategies.

MOTS-c as a means of protecting the lungs from oxidative and inflammatory lung damage

Studies have also demonstrated a novel role for MOTS-c as a key protective signal in lung damage caused by ischemia and reperfusion, inflammation, infection, surgery and radiation exposure. In experimental models and clinical observations, MOTS-c consistently preserves lung barrier integrity, reduces oxidative stress and limits cell death due to inflammation and ferroptosis. A major theme is MOTS-c's ability to translocate into the cell nucleus or activate cytoprotective signaling networks, leading to significant induction of antioxidant and restorative pathways. Importantly, MOTS-c levels in the bloodstream closely mirror lung injury risk and recovery, highlighting its potential as both a therapeutic mediator and an early biomarker.

Li et al (2025) investigated how MOTS-c protects the lungs from ischemia-reperfusion injury, a serious condition that can lead to acute respiratory failure after heart and lung surgery [37]. In rat models and cellular experiments, lung injury caused severe oxidative stress and damage to the pulmonary barrier. However, endothelial cells increased their own levels of MOTS-c, which was associated with improved tissue structure. Under hypoxic stress and subsequent reoxygenation, MOTS-c penetrated into the cell nucleus via a pathway involving the cytoskeletal protein MYH9. This process depended on oxidative stress-induced signaling and enabled MOTS-c to bind to regions of cell nucleus DNA that control antioxidant genes. As a result, key protective genes such as HMOX1 and NQO1 were activated, increasing the antioxidant capacity of the lung and reducing damage. When MOTS-c was administered externally, lung inflammation and oxidative damage were reduced, barrier function was preserved and survival improved. In patients undergoing cardiopulmonary bypass, an increase in blood levels of MOTS-c at 24 hours strongly predicted a lower risk of acute respiratory failure, outperforming standard markers. Taken together, these results demonstrate that MOTS-c protects the lungs by entering the cell nucleus to enhance antioxidant defense, and may serve as an early clinical biomarker of lung injury risk.

Similarly, Zhang et al (2025) investigated whether MOTS-c protects the airway lining in allergic asthma, a disease characterized by chronic inflammation and impaired barrier function [38]. Patients with asthma showed lower blood levels of MOTS-c than healthy subjects. In mouse models exposed to house dust mite allergens, MOTS-c treatment reduced lung inflammation, oxidative stress and tissue damage. Importantly, MOTS-c restored the tight junction proteins that hold airway cells together, and improved mitochondrial health. In bronchial epithelial cells treated with MOTS-c at a concentration of 10 μM, cell death and oxidative damage were significantly reduced. However, these protective effects disappeared in animals lacking Nrf2, a master antioxidant regulator. This confirmed that MOTS-c requires Nrf2 activation to maintain airway barrier integrity. Overall, the study shows that MOTS-c protects the airways by enhancing antioxidant defenses, preventing cell death, and maintaining mitochondrial and epithelial function in allergic asthma.

In another related study, Wang et al (2025) investigated whether MOTS-c is the circulating factor responsible for the protective effect of remote ischemic preconditioning, a procedure known to limit organ damage after blood flow interruption [39]. In lung transplant patients, MOTS-c levels dropped sharply after ischemia-reperfusion injury. However, after pre-conditioning before surgery, MOTS-c levels in the bloodstream increased and lung injury was reduced. Similar results were observed in mouse models, where preconditioning or direct injection of MOTS-c reduced inflammation, vascular leakage and lung injury. Importantly, administration of MOTS-c alone reproduced the protective effects of preconditioning. Mechanistic studies showed that MOTS-c protected endothelial barrier function by increasing Nrf2 levels. When Nrf2 was blocked or genetically deleted, MOTS-c ceased to function. These findings indicate that MOTS-c is a key blood-borne signal that mimics preconditioning and protects the lung by maintaining endothelial stability through Nrf2 activation.

In addition, Yin et al (2020) investigated whether MOTS-c could protect against acute lung injury caused by bacterial toxins [40]. Mice received MOTS-c at a dose of 5 mg per kg of body weight by injection, twice daily for six days before exposure to toxins. Pretreatment reduced weight loss, pulmonary edema and infiltration of immune cells that cause inflammation. MOTS-c also decreased harmful inflammatory signals such as TNF-α, IL-1β and IL-6, while increasing protective factors such as IL-10 and antioxidant enzymes. At the level of signaling, MOTS-c activated AMPK and SIRT1, pathways related to energy balance and stress resistance. At the same time, it inhibited MAPK, NF-κB and STAT3 pathways that cause inflammation and tissue damage. Taken together, these results show that MOTS-c protects the lungs from severe inflammatory damage by restoring metabolic balance, reducing oxidative stress and calming excessive immune responses.

In addition, Shen et al (2025) investigated whether MOTS-c can protect the lungs from damage caused by extracorporeal circulation, a common complication after heart surgery [41]. In a clinical trial involving 107 patients, those who developed acute lung injury had significantly lower levels of MOTS-c in their blood. This suggested that low levels of MOTS-c increase susceptibility to lung injury. To investigate the causes of this phenomenon, the researchers used animal and cellular models of lung injury caused by ischemia and reperfusion. Administration of MOTS-c prior to injury markedly reduced lung tissue damage, inflammation and oxidative stress. Mechanistically, MOTS-c restored normal energy consumption in lung vascular cells by stimulating glycolysis, a process that converts sugar into usable energy. This occurred through activation of the AMPK-HIF-1α-PFKFB3 pathway, which preserved ATP levels and reduced harmful lipid oxidation. As a result, a form of iron-induced cell death called ferroptosis was strongly inhibited. Importantly, blocking PFKFB3 eliminated these benefits, confirming that restoring glycolysis is essential for MOTS-c protection. Overall, these results show that MOTS-c protects the lungs after heart surgery by restoring energy balance and preventing ferroptotic damage.

Similarly, Lu et al (2023) investigated whether MOTS-c could prevent lung damage caused by myocardial ischemia and reperfusion, which often occurs during heart surgery [42]. In patients, lower MOTS-c levels after surgery were associated with higher oxidative stress. In rats, ischemia and reperfusion caused severe lung damage and strong activation of ferroptosis. However, after the initial administration of MOTS-c to the animals, the lung damage was significantly reduced. Tissue structure improved, oxidative stress decreased and ferroptosis-related genes were inhibited. In lung epithelial cells exposed to hypoxia and reoxygenation, MOTS-c directly prevented cell death due to ferroptosis. These protective effects required activation of the PPARγ pathway. Once PPARγ signaling was blocked, MOTS-c ceased to function. Taken together, these results indicate that MOTS-c protects the lungs after cardiac ischemia by inhibiting ferroptosis through PPARγ activation.

In another model of acute lung injury, Wen et al (2024) studied the damage caused by bacterial peptides that breach the pulmonary vascular barrier [43]. Exposure to bacterial fMLP signaling induced severe inflammation, oxidative stress, ferroptosis and breakdown of tight endothelial junctions. This damage was dependent on FPR2 receptor activation and dysregulation of Nrf2 and MAPK signaling. After MOTS-c administration, these deleterious effects were significantly reversed. In both rat and human lung endothelial cells, MOTS-c reduced ferroptosis, lowered inflammatory signals and restored barrier proteins that prevent fluid leakage. As a result, blood vessel integrity was preserved and lung damage was reduced. These findings indicate that MOTS-c is a potent protective agent against infection-related lung damage caused by ferroptosis and barrier failure.

In addition, Zhang et al (2024) investigated whether MOTS-c could protect against radiation pneumonitis, a serious complication of thoracic radiotherapy [44]. Mice received a high dose of radiation to the lungs and then were treated with daily injections of MOTS-c for two weeks. Radiation caused severe lung inflammation, oxidative stress, mitochondrial damage and epithelial cell death. However, MOTS-c treatment significantly reduced tissue damage and inflammatory infiltration. Lung cell mitochondria remained intact and cell death was reduced. In cellular studies, MOTS-c directly protected lung epithelial cells from radiation-induced oxidative stress and mitochondrial dysfunction. Mechanistically, MOTS-c activated Nrf2 and promoted its movement into the cell nucleus, enhancing antioxidant protection. In the absence of Nrf2, MOTS-c no longer provided protection. These results show that MOTS-c protects the lung from radiation damage by maintaining mitochondrial health and activating Nrf2-dependent antioxidant pathways.

MOTS-c in pain modulation and inflammation control

Several studies have found that MOTS-c acts as a potent regulator of pain and inflammation in cancer, neuropathic and inflammatory disease models. Reduced levels of endogenous MOTS-c are consistently associated with increased pain sensitivity, while supplementation with the peptide significantly relieves pain without opioid-like side effects. Mechanistically, MOTS-c acts through AMPK-dependent pathways to restore mitochondrial function, inhibit excessive immune cell activation and reduce inflammatory signaling in both central and peripheral tissues. In parallel, MOTS-c protects vulnerable cells by enhancing antioxidant protection and reducing stress-induced damage.

Yang et al (2024) investigated whether MOTS-c can reduce cancer-induced bone pain, which is severe and persistent pain caused by bone metastasis [45]. In mice with cancer-induced bone pain, natural levels of MOTS-c were significantly lower than normal. When MOTS-c was injected, pain symptoms such as sensitivity to touch were markedly reduced. However, after blocking AMPK, the pain-relieving effects disappeared, indicating that AMPK activation is essential. Further analysis showed a dual effect. In the spinal cord, MOTS-c restored mitochondrial renewal, reduced activation of pain-inducing immune cells called microglia, and lowered inflammatory signals that sensitize neurons. At the same time, in the bone environment, MOTS-c reduced bone destruction by upregulating bone resorbing cells and calming local immune activity. Importantly, long-term treatment did not damage liver, kidney, heart or lipid levels. Taken together, these results indicate that MOTS-c reduces cancer-related bone pain by improving mitochondrial health and inhibiting inflammation through AMPK signaling.

In a related pain model, Jiang et al (2023) investigated whether MOTS-c could alleviate neuropathic pain caused by nerve damage [46]. Mice with nerve damage showed reduced levels of MOTS-c in both blood and spinal cord tissue. When MOTS-c was injected directly into the spinal cord, pain sensitivity decreased in a markedly dose-dependent manner. These effects were blocked by the AMPK inhibitor, but were unaffected by opioid blockers, showing that MOTS-c does not act like opioid analgesics. Mechanistically, MOTS-c activated AMPK in the spinal cord, reduced microglia activation and decreased inflammatory cytokines. In addition, it directly protected neurons by reducing oxidative damage and lowering the expression of c-Fos, a marker of neuronal activation associated with pain. Compared to morphine, MOTS-c caused fewer side effects and showed no signs of tolerance. These results identify MOTS-c as a non-opioid, AMPK-dependent therapy for chronic neuropathic pain.

In addition to pain, Jiang et al (2023) also studied MOTS-c in inflammatory bowel disease using a colitis model [47]. MOTS-c injection significantly reduced weight loss, diarrhea, shortening of the colon and tissue damage. It lowered inflammatory cytokine levels, reduced immune cell infiltration and prevented excessive cell death in the intestinal lining. These effects included inhibition of inflammatory signaling associated with AMPK and stress-activated kinases. However, oral administration of MOTS-c alone was ineffective due to poor stability. To address this problem, the researchers developed an orally active analog of MOTS-c with better absorption. This modified peptide significantly alleviated colitis symptoms after oral administration. These findings underscore both the anti-inflammatory potential of MOTS-c and the importance of administration strategies in peptide therapies.

In addition, Shen et al (2022) focused on myocardial cells exposed to oxidative and inflammatory stress [48]. When the cells were damaged by hydrogen peroxide, pretreatment with MOTS-c restored cell survival, reduced the amount of harmful oxidative molecules and lowered the level of inflammatory cytokines. MOTS-c reactivated the Nrf2 antioxidant system while inhibiting the signaling of NF-κB, the main inducer of inflammation. When Nrf2 was silenced or NF-κB was induced, MOTS-c lost most of its protective effect. These results show that MOTS-c protects cardiac cells by enhancing internal antioxidant defenses while reducing inflammation.

In another study, Wang et al (2024) further investigated whether MOTS-c could reduce inflammatory pain through both central and peripheral effects [49]. In multiple pain models, MOTS-c strongly reduced pain behavior. When administered centrally, it reduced inflammatory cytokine levels in the spinal cord, inhibited glial activation and reduced excessive excitability of pain processing neurons. When administered topically, it reduced inflammation in peripheral tissues and inhibited nerve endings that transmit pain signals. This dual action shows that MOTS-c interrupts the transmission of pain signals at multiple levels, from damaged tissue to processing centers in the spinal cord.

In addition, Yin et al. (2020) evaluated MOTS-c in an inflammatory pain model using formalin injection [50]. MOTS-c reduced pain symptoms in a clearly dose-dependent manner, showing a strong effect at a dose of 50 mg/kg. Blocking AMPK resulted in the loss of this beneficial effect, confirming the pathway dependence. MOTS-c also altered immune signaling toward an anti-inflammatory profile and reduced activation of pain-related pathways in the spinal cord. Taken together, these results indicate that MOTS-c reduces inflammatory pain by activating AMPK and inhibiting stress-related signaling cascades.

Neuroprotective effects of MOTS-c in oxidative stress, neuroinflammation and cognitive impairment

Studies have shown that MOTS-c protects the brain from oxidative damage, inflammation and functional deterioration in multiple models of neurological stress. Under experimental conditions, MOTS-c preserves mitochondrial integrity, activates antioxidant defense systems and limits damage to vulnerable neuronal populations, such as dopamine-producing cells. In parallel, MOTS-c improves cognitive performance by inhibiting neuroinflammation and restoring energy sensing pathways essential for memory and learning. Importantly, MOTS-c also maintains the integrity of the blood-brain barrier during severe systemic inflammation, preventing secondary brain damage.

Xiao et al (2023) investigated whether MOTS-c can protect dopamine-producing brain cells from toxic damage, a key problem in Parkinson's disease [51]. In cell and animal models exposed to rotenone, a toxin that damages mitochondria, MOTS-c levels were disrupted and the peptide moved from the mitochondria to the cell nucleus. In the nucleus, MOTS-c directly interacted with Nrf2, a major antioxidant switch. This interaction activated protective genes such as HO-1 and NQO1, which help neutralize harmful oxidative stress. When MOTS-c was administered before exposure to the toxin, brain cells showed better mitochondrial function and less oxidative damage. In rats, MOTS-c preserved dopamine-related markers in the brain and restored antioxidant signaling that had been suppressed by rotenone. At the same time, the concentration of Keap1, a Nrf2-blocking protein, decreased. Overall, these results show that MOTS-c directly enhances antioxidant protection and protects dopamine neurons by stabilizing mitochondrial health.

In addition, Jiang et al (2021) further investigated how MOTS-c affects learning and memory, especially during inflammation or amyloid-related brain stress [52]. When native MOTS-c was administered directly to the brain ( ), memory improved in both object recognition and spatial tasks. MOTS-c also reversed memory deficits caused by amyloid-β and bacterial inflammation. These benefits disappeared when AMPK was blocked, confirming that AMPK activation is necessary. In the hippocampus, MOTS-c increased AMPK signaling while decreasing activation of astrocytes and microglia, immune cells responsible for brain inflammation. As a result, inflammatory cytokine levels decreased. Since native MOTS-c does not readily enter the brain after systemic administration, the researchers developed a cell-penetrating analog. This modified peptide reached the brain after intranasal or intravenous administration and caused significant improvements in memory while reducing neuroinflammation. These results point to MOTS-c, and especially its brain-penetrating analog, as a promising approach for treating memory loss associated with inflammation or amyloid stress.

In addition, Bai et al (2025) investigated whether MOTS-c can protect the brain during sepsis, a life-threatening condition that often causes brain damage by breaking down the blood-brain barrier [53]. Mice exposed to bacterial toxins were given MOTS-c at a dose of 20 mg/kg four hours before damage. The treatment significantly improved survival and reduced neurological impairment. Brain tissue showed less structural damage and lower levels of inflammatory cytokines. Importantly, MOTS-c preserved the blood-brain barrier, as evidenced by reduced leakage, less brain swelling and stronger expression of barrier-forming proteins. Markers of healthy blood vessels and supporting cells were also restored. In parallel, astrocyte and microglia activation was inhibited, while protective growth factors that promote neuronal survival were increased. Taken together, these results indicate that MOTS-c protects the brain in sepsis by attenuating inflammation, strengthening the blood-brain barrier and promoting neurological regeneration.

Figure 3 The role of MOTS-c in pain perception and protection (based on animal studies)

Protective and antitumor role of MOTS-c in metabolic stress, viral stress and hypoxia

Many scientific studies have described the multifaceted effects of MOTS-c in liver diseases, including metabolic damage, viral infections and cancer-related stress. In metabolic liver disorders, MOTS-c restores mitochondrial function, reduces inflammation and fibrosis, and protects hepatocytes from programmed cell death by stabilizing key survival proteins. In parallel, MOTS-c counteracts hypoxia-induced resistance mechanisms in liver cancer by reactivating apoptosis pathways and reducing tumor growth. Clinical and experimental evidence also supports the role of MOTS-c as a biomarker and antiviral mediator in chronic hepatitis B.

Lu et al (2024) investigated whether MOTS-c can slow or reverse non-alcoholic steatohepatitis, a progressive steatohepatic disease caused by mitochondrial damage, inflammation, cell death and scarring [54]. In mice fed a diet inducing NASH, both prophylactic and therapeutic MOTS-c regimens significantly reduced liver fat accumulation, inflammation, cell death and fibrosis. Detailed metabolic studies showed that MOTS-c restored mitochondrial energy production and corrected the metabolic defects caused by NASH. A key finding was that MOTS-c bound directly to Bcl-2, a protein that protects cells from death. By stabilizing Bcl-2 and preventing its degradation, MOTS-c protected liver cells from mitochondrial stress and apoptosis. When Bcl-2 was blocked or silenced, the benefits of MOTS-c largely disappeared. Taken together, these results show that MOTS-c slows the progression of NASH by stabilizing Bcl-2, restoring mitochondrial function, and reducing inflammation and fibrosis.

In a related cancer study, Shen et al (2025) investigated whether MOTS-c can overcome resistance to programmed cell death in liver cancer under low oxygen conditions [55]. Patients with hepatocellular carcinoma had lower levels of MOTS-c in their blood than healthy subjects. In cancer cells cultured under hypoxic conditions, key death signals were suppressed, rendering the cells resistant to TRAIL-induced killing. MOTS-c treatment reversed this resistance by activating AMPK, which restored the activity of MEF2A, a transcription factor that turns on death receptors DR4 and DR5. As a result, the tumor cells regained sensitivity to TRAIL and showed a higher rate of apoptosis. In mice with tumors, MOTS-c also reduced hypoxia-induced tumor growth. These findings show that MOTS-c restores the sensitivity of cancer cells to treatment by reactivating a key apoptosis pathway suppressed by hypoxia.

In addition, Lin et al (2024) examined MOTS-c in hepatitis B virus infection, focusing on both diagnostic value and antiviral activity [56]. In a large cohort of patients, MOTS-c levels were significantly lower in infected individuals and strongly inversely correlated with viral titer. As a biomarker, MOTS-c showed high accuracy in distinguishing chronic hepatitis B from healthy controls and in separating immunologically active from inactive disease states. In experimental models, MOTS-c reduced viral replication by 50-70%, while improving liver function without detectable toxicity. Mechanistically, MOTS-c enhanced mitochondrial biogenesis and activated MAVS-dependent antiviral signaling. A key finding was that MOTS-c regulated MYH9-actin-driven mitochondrial remodeling, which helped maintain mitochondrial health and promoted antiviral defense. These findings identify MOTS-c as a promising biomarker and potential therapeutic agent for the treatment of chronic hepatitis B.

Systemic regulatory functions of MOTS-c in immunity, endocrine control, aging and tissue protection

In other studies, researchers have highlighted the broad systemic effects of MOTS-c and its role in immune defense, neuroendocrine control, tissue protection, aging and tumor suppression. In various models of disease and stress, MOTS-c enhances host immunity by balancing the immune response, maintaining mitochondrial integrity and stabilizing genetic programs essential for tissue survival and regeneration. The central and peripheral actions of MOTS-c coordinate energy expenditure, hormonal signaling, reproductive function and developmental protection under physiological and pathological stress. In parallel, MOTS-c reduces degenerative changes in aging tissues and inhibits tumor growth through targeted molecular interactions.

An earlier study by Zhai et al (2017) looked at whether MOTS-c could improve the outcome of severe bacterial infections [57]. In mice infected with drug-resistant Staphylococcus aureus MOTS-c treatment significantly increased survival rates and reduced the bacterial burden. This protection was accompanied by lower levels of harmful inflammatory cytokines and higher levels of the anti-inflammatory cytokine IL-10. MOTS-c also enhanced the ability of macrophages to kill, improving the body's ability to fight infection. At the level of signaling, MOTS-c inhibited MAPK activation, which causes excessive inflammation, while increasing the activity of AhR and STAT3, pathways that help restore immune balance. Taken together, these results show that MOTS-c improves survival in severe infections by enhancing immune function while preventing harmful inflammation.

In addition, Bahar et al (2023) investigated how MOTS-c acts through the central nervous system to regulate energy balance and thyroid function [58]. Male rats were injected with MOTS-c into the brain ventricles at a concentration of 10 μM or 100 μM. After treatment, food intake increased, but body weight did not change, suggesting a compensatory increase in energy consumption. MOTS-c significantly reduced blood levels of TSH, T3 and T4, indicating inhibition of the hypothalamic-pituitary-thyroid axis. Despite this reduction in hormone levels, MOTS-c increased the expression of UCP1 in adipose tissue and UCP3 in skeletal muscle. These proteins promote heat production by mitochondria and energy dissipation. The results show that centrally administered MOTS-c reduces thyroid hormone signaling while increasing peripheral mitochondrial thermogenic activity, highlighting its role as a central regulator of energy metabolism.

In addition, Waldmann et al (2023) investigated whether MOTS-c could protect hair cells from gentamicin-induced damage, a major cause of permanent hearing loss [59]. Using explants of the organ of Corti, the study showed that exogenous MOTS-c significantly protected hair cells from death after exposure to gentamicin. Mechanistically, MOTS-c increased phosphorylation of AMPKα, a key pathway for energy sensing and stress resistance. This mechanism differed from the action of humanin, which acted through AKT signaling. Preservation of ciliary cell integrity indicates that MOTS-c improves cellular resistance to ototoxic stress. These findings confirm that peptides of mitochondrial origin may be potential protective agents against drug-induced hearing loss. In addition, Zhong et al (2022) investigated whether MOTS-c could prevent heart failure caused by chronic pressure overload [60. Mice underwent transverse aortic constriction to induce pathological cardiac stress and were administered MOTS-c continuously via subcutaneous osmotic pumps. MOTS-c treatment preserved cardiac function, reduced ventricular remodeling and reduced fibrosis and inflammatory infiltration. Oxidative damage to cardiac tissue was also significantly reduced. At the molecular level, MOTS-c activated AMPK signaling. In cultured cardiomyocytes, MOTS-c protected against hydrogen peroxide-induced apoptosis through the same pathway. These results show that MOTS-c prevents pressure-induced heart failure by reducing oxidative stress, inflammation and cell death, while maintaining cardiac energy balance.

In addition, Yu et al (2021) studied the effects of MOTS-c on aging human placenta-derived mesenchymal stem cells [61]. MOTS-c treatment restored youthful cell morphology and improved mitochondrial function and metabolism. MOTS-c activated AMPK and inhibited mTORC1 signaling, a pathway often overactive in aging cells. Mitochondrial respiration and reactive oxygen species production were reduced, indicating improved mitochondrial efficiency. Lipid synthesis was also inhibited, correcting another feature of aging cells. Overall, MOTS-c changed aging stem cells into a metabolic state resembling young cells. These findings suggest that MOTS-c can restore metabolic and mitochondrial homeostasis in aging human stem cells.

In addition, Ozturk et al (2024) examined how central administration of MOTS-c affects male sex hormones under normal and obese conditions [62]. Rats received MOTS-c into the brain ventricles at a dose of 10 μM or 100 μM for 14 days. MOTS-c significantly increased GnRH gene and protein expression in the hypothalamus in both obese and non-obese animals. This was followed by an increase in blood levels of testosterone, luteinizing hormone and folliculotropic hormone, indicating activation of the hypothalamic-pituitary-gonadal axis. Although the responses were stronger in non-obese rats, the obese animals still showed a marked increase in hormone levels. These results show that centrally acting MOTS-c stimulates the release of sex hormones even in endocrine disorders associated with obesity, allowing MOTS-c to be considered a central regulator of male reproductive function.

Interestingly, Chen et al (2026) investigated whether MOTS-c could protect the placenta from damage caused by low oxygen levels during pregnancy, leading to intrauterine growth restriction [63]. Pregnant mice were exposed to hypoxia from mid to late gestation, and some of them received MOTS-c at a dose of 5 mg/kg. Hypoxia caused a sharp decrease in MOTS-c levels in the placenta, and the lower levels were directly correlated with decreased fetal weight. MOTS-c treatment significantly improved fetal growth and reduced placental damage. Blood vessel formation in the placenta improved, oxidative stress was reduced and tissue structure was preserved. These benefits disappeared in Nrf2-deficient mice and in Nrf2-inhibitor-treated endothelial cells, showing that Nrf2 activation is essential. The results show that MOTS-c protects placental function under hypoxic stress by activating antioxidant defense mechanisms and promoting healthy placental blood flow.

In addition, Wang et al (2024) investigated whether MOTS-c can protect male reproductive function after exposure to chemotherapy in early life [64]. Pre-pubertal male mice received cyclophosphamide, which caused permanent testicular damage and impaired sperm development. MOTS-c treatment significantly preserved testicular structure and spermatogenesis. Key genes necessary for germ cell maintenance, hormone regulation and tissue development were restored to normal levels. These included Piwil2, AGT and PTGDS, which had been disrupted by chemotherapy. The results show that MOTS-c helps stabilize mitochondrial function and gene expression during testicular development, promoting long-term reproductive health after chemotherapy.

In another study, Li et al (2019) investigated whether MOTS-c could reverse early aging-related changes caused by long-term exposure of mice to D-galactose [65]. The aging model resulted in abnormal fat accumulation in the liver, visceral fat and skin, as well as intestinal damage and impaired cellular renewal. Mitochondrial structure and dynamics were also disrupted in many tissues. MOTS-c treatment significantly reduced abnormal lipid accumulation, restored a healthier mitochondrial shape and normalized genes controlling mitochondrial division and fusion. In the intestine, tissue structure improved, cell proliferation increased and markers of DNA damage associated with aging decreased. Although the changes in body weight and blood sugar levels were small, MOTS-c showed strong protection at the tissue level against early aging-related damage.

In addition, Yin et al (2024) investigated the role of MOTS-c in ovarian cancer progression [66]. Ovarian cancer patients had significantly lower levels of MOTS-c in blood and tumor tissue, and low expression was associated with worse survival. In tumor cell models, MOTS-c strongly reduced cell growth, migration and invasion, while increasing programmed cell death and arresting cell cycle progression. Mechanistically, MOTS-c bound to the oncogenic protein LARS1 and promoted its degradation by blocking the stabilizing effect of deubiquitinase USP7. This led to downregulation of LARS1, which is known to stimulate tumor growth. In mouse models of cancer, MOTS-c treatment significantly reduced tumor size without detectable toxicity. These findings identify MOTS-c as a potent inhibitor of ovarian cancer growth through targeted destabilization of a key tumor-promoting protein.

Table 1. Summary of the biological role of MOTS-c in various organ systems and disease models 

Is MOTS-c a supplement?

Not
MOTS-c is not an approved dietary supplement, nutraceutical, functional food or vitamin. It is a mitochondria-encoded signal peptide consisting of 16 amino acids, produced endogenously in human and animal cells from a short open reading frame (sORF) in the mitochondrial 12S rRNA gene. Biologically, MOTS-c functions as a mitokine - a hormone-like mitochondrial signal that regulates cellular responses to stress, energy metabolism and gene expression - rather than as a nutrient derived from food.

Products sold online as „MOTS-c” are almost always labeled „for research use only (RUO),” meaning they are not approved or intended for human consumption. The RUO designation also means that these products are not subject to regulatory standards applicable to dietary supplements or pharmaceutical products, including requirements for:

• Manufacturing under GMP conditions for food or drugs,
• Verification of identity, purity and cohesion between parties,
• Toxicological studies, stability studies or long-term safety assessment,
• approved dosage, instructions for use or health claims.

Importantly, MOTS-c is not a food ingredient and does not meet the regulatory definitions used by regulatory agencies (such as the FDA or EFSA) for supplements that must be derived from food sources or essential nutrients (e.g., vitamins, minerals, amino acids, plant substances). None of the experimental, preclinical or translational studies reviewed describe MOTS-c as food-derived, nutritionally essential or suitable for oral supplementation. Instead, virtually all studies treat MOTS-c as an experimental bioactive peptide administered by controlled laboratory routes (e.g., injections) to investigate its biological signaling role.

Is MOTS-c used for fat loss or weight loss?

There is no approved, proven or clinically validated use of MOTS-c for fat or weight reduction in humans. Although MOTS-c has attracted attention for its metabolic effects, all evidence of effects on obesity comes from animal models and mechanistic laboratory studies, not from human intervention studies. As such, MOTS-c should not be considered a weight-loss agent.

Preclinical studies show that MOTS-c modulates lipid metabolism, rather than directly inducing weight loss. In mice and rats, MOTS-c has been shown to improve fatty acid oxidation, enhance thermogenic signaling in adipose tissue, reduce lipid infiltration in skeletal muscle and liver, and promote metabolic flexibility during nutritional or energy stress. These effects reflect improvements in metabolic efficiency and tissue health, rather than pharmacological fat reduction.

What is equally important is what the studies do not show. There are no controlled human studies showing reductions in body fat, body weight or waist circumference after MOTS-c administration. No study has shown clinically significant weight loss or compared MOTS-c with standard weight loss methods. Claims circulating on the Internet are therefore extrapolations of animal data or anecdotal reports, not conclusions based on evidence supported by human studies.

What is the recommended dose of MOTS-c?

There is no recommended or approved dose of MOTS-c for humans. To date, no regulatory agency - including the FDA, EMA, MHRA or other national agencies - has established guidelines for MOTS-c dosing in humans.

All doses reported in the scientific literature are experimental and context-specific, derived only from animal studies or cell culture experiments. In rodents, MOTS-c is typically administered at doses ranging from about 5 to 20 mg/kg, depending on the disease model and duration of treatment. In vitro studies use concentrations in the nanomolar to micromolar range, which cannot be translated to human dosing.

Importantly, there have been no pharmacokinetic studies in humans determining absorption, distribution, metabolism or clearance. As a result, there are no scientifically established safe starting doses, maximum tolerated doses, dosing frequencies or duration of treatment in humans. Any dosing protocols available on the Internet are therefore not supported by clinical evidence.

Is there a MOTS-c dosage table?

There is no standard, medically approved or evidence-based MOTS-c dosage table. Any dosage tables available on the Internet are unofficial, speculative and not based on human data.

These tables are not supported by human pharmacokinetic studies, toxicology studies, dose escalation studies or clinical guidelines. They are usually extrapolated from animal studies without the use of safety margins, interspecies scaling or regulatory frameworks required for use in humans . The use of such tables for self-administration of the drug carries unknown and potentially serious risks, as neither safety nor efficacy has been established.

How is MOTS-c administered in research?

In almost all in vivo experimental studies, MOTS-c is administered by the injection route, most commonly intraperitoneal (IP) or intravenous (IV). Studies involving the central nervous system have also used intrathecal or intracerebral administration to provide direct access to neural tissue.

These routes were chosen because MOTS-c is a small peptide that degrades rapidly in the gastrointestinal tract and requires systemic bioavailability to exert its signaling effects. Administration by injection allows researchers to precisely control exposure and duration of action - conditions that cannot be achieved with oral administration of native MOTS-c.

Can MOTS-c be taken orally?

Native MOTS-c has poor bioavailability after oral administration and is not considered suitable for oral administration. Studies indicate that orally administered MOTS-c undergoes rapid enzymatic degradation in the gastrointestinal tract, resulting in minimal systemic absorption.

To address this limitation, researchers have explored modified or cell-penetrating MOTS-c analogs, including peptide-conjugated versions designed to enhance stability and tissue absorption. However, these approaches remain experimental, have not been approved in humans and are not approved for clinical or consumer use. Currently, oral MOTS-c cannot be considered a reliable or evidence-based method of administration.

What is the half-life of MOTS-c?

MOTS-c appears to have a short biological half-life, based on a wealth of experimental evidence. Animal studies show rapid clearance from the body, requiring repeated dosing to maintain biological effects. In addition, endogenous levels of MOTS-c increase transiently in response to metabolic stress or exercise and then decrease, consistent with a short-acting signaling molecule.

However, exact values for the half-life in humans have not been determined, as no formal pharmacokinetic studies have been conducted in humans. Until such studies are conducted, the exact duration of action, clearance rate and exposure profile in humans remain unknown.

Is MOTS-c used in bodybuilding?

MOTS-c is sometimes discussed in bodybuilding and fitness circles, mainly in relation to endurance, metabolic performance and fat metabolism. These discussions are speculative and based mainly on animal studies or anecdotal self-reports.

Scientifically, MOTS-c is not an approved performance-enhancing substance, and no human clinical studies have shown increases in muscle mass, hypertrophy, maximal strength or athletic performance after MOTS-c administration. Currently, claims linking MOTS-c to bodybuilding performance are not supported by clinical evidence.

Does MOTS-c have side effects?

In animal models, MOTS-c is generally well tolerated. Studies have shown no apparent organ toxicity, significant changes in blood pressure, or consistent adverse effects on markers of liver and kidney function during short-term administration.

However, the lack of safety data in humans is a major limitation. There have been no long-term safety studies, chronic exposure studies, or assessments of reproductive toxicity, carcinogenicity, or drug-peptide interactions in humans. Importantly, lack of evidence does not imply safety, and long-term risks to humans remain unknown.

Is it legal to purchase MOTS-c?

MOTS-c is most often marketed as an investigational peptide, labeled „not for human use” or „for research use only (RUO).” Its regulatory status varies by country, intended use and marketing claims.

MOTS-c is not approved as a drug, dietary supplement or medical therapy in any jurisdiction. Although possession of MOTS-c for research purposes may be legal in some regions, the sale or use of MOTS-c for human consumption falls outside the approved regulatory framework.

How is MOTS-c different from NAD⁺?

MOTS-c and NAD⁺ refer to mitochondrial function, but are fundamentally different molecules. NAD⁺ is a metabolic coenzyme derived from vitamin B3 that is directly involved in redox reactions and energy transfer. In contrast, MOTS-c is a mitochondria-encoded signal peptide that acts as a hormone-like mitokine to regulate gene expression, stress responses and metabolic adaptation.

NAD⁺ precursors are legally sold as dietary supplements in many countries, while MOTS-c is not approved for use as a dietary supplement or for medical use. Their biological roles are complementary, but they are not interchangeable.

Is MOTS-c approved for medical use?

No. MOTS-c remains in the preclinical and translational research phase. It is not approved for the diagnosis, prevention or treatment of any disease and is not included in clinical practice guidelines. All current applications are investigational in nature.

Who should avoid MOTS-c?

Because MOTS-c is an experimental peptide that has not been approved for use in humans, it should be avoided by pregnant or breastfeeding women, people with chronic medical conditions, people taking prescription drugs and anyone without qualified medical supervision. Experimental peptides should only be used and administered under controlled research conditions and not for unsupervised use alone.

Disclaimer

This article was written for educational purposes and is intended to raise awareness of the substance under discussion. It is important to note that the article is about the substance in general - it is not a description of a specific product (chemical reagent). We do not suggest using chemical reagents on humans - this is prohibited by law. For a product to be used for treatment, it must be registered as a drug. The information in the text is based on available scientific research and is not intended to serve as medical advice or promote self-medication. The reader should consult any health and treatment decisions with a qualified health professional.

References

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58. Bahar, M. R., Tekin, S., Beytur, A., Onalan, E. E., Ozyalin, F., Colak, C., and Sandal, S. (2023). Effects of intrathecal MOTS-c infusion on thyroid hormones and uncoupling proteins. Biology of the Future, 74(1-2), 159-170. https://doi.org/10.1007/s42977-023-00163-6 
59. Waldmann, D., Lu, Y., Cortada, M., Bodmer, D., and Levano Huaman, S. (2023). Exogenous humanin and MOTS-c act as protective agents against gentamicin-induced ciliary cell damage. Biochemical and Biophysical Research Communications, 678, 115-121. https://doi.org/10.1016/j.bbrc.2023.08.033 
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63. Chen, D., Zhao, H.-M., Sun, X.-L., Xing, Z.-X., Li, S.-P., Li, S.-C., Wu, Y.-X., Pang, Q.-F. & Huang, J.-F. (2026). MOTS-c protects against placental damage via Nrf2 activation in hypoxia-induced intrauterine growth restriction mice. International Journal of Molecular Medicine, 57(1), 26. https://doi.org/10.3892/ijmm.2025.5697 
64. Wang, J., Wen, W., Liu, L., He, J., Deng, R., Su, M., Zhao, S., Wang, H., Rao, M., & Tang, L. (2024). Effects of humanin and MOTS-c on ameliorating reproductive damage induced by prepubertal cyclophosphamide chemotherapy in male mice. Reproductive Toxicology, 129, 108674. https://doi.org/10.1016/j.reprotox.2024.108674 
65. Li, Q., Lu, H., Hu, G., Ye, Z., Zhai, D., Yan, Z., Wang, L., Xiang, A. and Lu, Z. (2019). Previous changes in mice after D-galactose administration were improved by MOTS-c, a small mitochondria-derived peptide. Biochemical and Biophysical Research Communications, 513(2), 439-445. https://doi.org/10.1016/j.bbrc.2019.03.194
66. Yin, Y., Li, Y., Ma, B., Ren, C., Zhao, S., Li, J., Gong, Y., Yang, H. and Li, J. (2024). Mitochondrial-derived MOTS-c peptide inhibits ovarian cancer progression by attenuating USP7-mediated LARS1 deubiquitination. Advanced Science, 11(43), e2405620. https://doi.org/10.1002/advs.202405620