MOTS-c

What it is

MOTS-c is a 16-amino-acid peptide encoded by a short open reading frame (sORF) within the 12S rRNA gene of the mitochondrial genome. Under metabolic stress (e.g., glucose restriction, oxidative stress, exercise), MOTS-c translocates from mitochondria to the nucleus, where it regulates nuclear gene expression—including genes bearing antioxidant response elements (ARE)—and interacts with stress-responsive transcription factors such as NRF2/NFE2L2. Its primary described cellular mechanism involves inhibition of the folate cycle and de novo purine biosynthesis, leading to AMPK activation. MOTS-c activates AMPK, which in turn regulates downstream effectors including PGC-1α, HIF-1α, mTORC1, and PFKFB3, thereby modulating energy metabolism, mitochondrial biogenesis, glycolysis, oxidative stress responses, inflammation, autophagy, and apoptosis. MOTS-c also functions as a host defense peptide with direct antibacterial activity against pathogens including E. coli and MRSA, targeting bacterial membranes via its hydrophobic and cationic domains, and modulates innate immune cell differentiation. MOTS-c facilitates plasma membrane repair via interaction with TRIM72 and plasma lipids, and interacts directly with intracellular proteins including Bcl-2, MYH9/actin complexes, LARS1, and KEAP1. Circulating MOTS-c is detected in plasma; levels decline with age and are reduced in numerous disease states.

Class: Mitochondrial-derived peptide (MDP) / Mitokine — 16-amino-acid peptide encoded within the 12S rRNA short open reading frame of the mitochondrial genome

What it's studied for

• Metabolic homeostasis, insulin resistance, and obesity Mixed
  • MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity; primary target organ is skeletal muscle; acts via folate-AICAR-AMPK pathway. PMID 25738459 Lee et al., Cell Metabolism 2015
  • MOTS-c prevented ovariectomy-induced obesity and insulin resistance in mice; activated AMPK pathway to improve energy dissipation and insulin sensitivity. PMID 30725119 Lu et al., J Mol Med 2019
  • MOTS-c increased mitofusion (OPA1, MFN2) and GLUT4 translocation in mammalian cells; MFN2 knockdown abrogated GLUT4 translocation. PMID 34253808 Bhullar et al., Sci Rep 2021
  • In 85 human subjects, serum MOTS-c levels were not significantly different between obese and normal-weight individuals; age and HOMA-IR were significant determinants of MOTS-c levels. PMID 41004666 Yildiz Ozkaya et al., Arch Endocrinol Metab 2025
• Type 2 diabetes mellitus and diabetic complications Mixed
  • Review summarising MOTS-c associations with T2DM risk factors and diabetic cardiomyopathy; compiles preclinical exogenous MOTS-c dosing schedules. PMID 41083123 Fang et al., Life Sci 2025
  • Review of MOTS-c research in type 1 and type 2 diabetes, highlighting regulatory roles in cellular metabolism and insulin action. PMID 36824008 Kong et al., Diabetes Metab J 2023
• Type 1 diabetes / autoimmune pancreatic islet protection Animal studies only
  • MOTS-c prevented autoimmune β-cell destruction in NOD mice by modulating T cell phenotype via TCR/mTORC1 signaling; T1D patients had lower serum MOTS-c than healthy controls. PMID 34320351 Kong et al., Cell Reports 2021
• Aging and physical performance / healthspan Mixed
  • MOTS-c enhanced physical performance in young, middle-age, and old mice; late-life intermittent MOTS-c treatment (3x/week) increased physical capacity and healthspan; exercise induces endogenous MOTS-c expression in human skeletal muscle and circulation. PMID 33473109 Reynolds et al., Nat Commun 2021
  • Review: plasma MOTS-c levels decline with age; MOTS-c has beneficial effects in age-related diseases including diabetes, cardiovascular disease, osteoporosis, postmenopausal obesity, and Alzheimer's. PMID 36761202 Zheng et al., Front Endocrinol 2023
  • Review: MOTS-c levels decline with age; aging characterized by gradual loss of mitochondrial metabolic balance potentially reversible with MOTS-c treatment. PMID 36233287 Mohtashami et al., IJMS 2022
• Skeletal muscle homeostasis, performance, and cachexia Mixed
  • MOTS-c augmented muscle mitochondrial bioenergetic performance via PGC-1α and AMPK in transgenic mice; lowered mitochondrial ROS emission and oxidative stress; no change in arterio-venous MOTS-c difference during exercise in humans. PMID 41520850 Gudiksen et al., Free Radic Biol Med 2026
  • Serum MOTS-c levels closely associated with aerobic exercise capacity in marathon runners; endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion and activating AMPK/PGC-1α. PMID 39706498 Feng et al., Free Radic Biol Med 2025
  • In physically active humans, serum MOTS-c positively correlated with average power, force, overall muscle mass, and leg muscle mass; no correlation with peak VO2. PMID 37834399 Domin et al., IJMS 2023
  • MOTS-c (15 mg/kg/2x day i.p.) partially preserved skeletal muscle mass in C26 tumor-bearing mice; attenuated cachexia-induced upregulation of Atrogin-1 and MuRF1; increased PGC-1α and AMPK phosphorylation in vitro. PMID 42266945 Jamnick et al., Front Med 2026
  • Wild-type MOTS-c increased myotube formation in human and murine muscle progenitor cells in vitro; blocked IL-6-induced STAT3 transcriptional activity via putative SH2 binding motif in the YIFY region. PMID 35842023 Garcia-Benlloch et al., Peptides 2022
• Cardiovascular disease (coronary artery disease, myocardial infarction, heart failure) Mixed
  • Lower circulating MOTS-c associated with impaired coronary endothelial function in humans; MOTS-c (2 µg/ml) improved vascular responsiveness to acetylcholine in rat and RAS-mouse aortic rings ex vivo. PMID 29242099 Qin et al., Int J Cardiol 2018
  • MOTS-c levels lower in stable CAD patients vs. controls (111±13 vs. 161±23); MOTS-c ≥130.9 had 80.3% sensitivity and 73.2% specificity for predicting CAD. PMID 36066139 Yasar et al., Eur Rev Med Pharmacol Sci 2022
  • MOTS-c levels significantly lower in STEMI group vs. controls; MOTS-c ≥84.15 pg/mL predicted no-reflow with 95.3% sensitivity and 88.9% specificity (AUC 0.95); strong independent predictor of in-hospital MACE. PMID 36629605 Cakmak et al., Arq Bras Cardiol 2023
  • MOTS-c deficiency persisted during cardiac de-acclimatization after high-altitude exposure in mice; exogenous MOTS-c activated PINK1/Parkin pathway, promoted mitophagy, and alleviated cardiac dysfunction; reduced circulating MOTS-c observed in patients with high-altitude heart disease and acute coronary syndrome. PMID 41654147 Feng et al., Free Radic Biol Med 2026
  • Plasma MOTS-c decreased in AF patients and inversely correlated with NT-proBNP; MOTS-c treatment reduced AF inducibility and attenuated atrial fibrosis and mitochondrial fission in mouse models. PMID 42193373 Liao et al., Biomedicines 2026
• Lung injury and respiratory diseases Mixed
  • Review: circulating MOTS-c levels reduced in acute respiratory distress; exogenous MOTS-c attenuates lung injury in preclinical models; MOTS-c decreased in COPD, OSA, and asthma; potentially increased in lung cancer. PMID 42243958 Amado et al., J Transl Med 2026
  • MOTS-c mediates RIPC-induced protection against lung ischemia-reperfusion injury via Nrf2 pathway in mice; serum MOTS-c decreased post-IR injury but increased with RIPC prior to lung transplantation. PMID 39827923 Wang et al., Free Radic Biol Med 2025
  • MOTS-c serum increments post-CPB (ΔMOTS-c) predicted ARDS with AUC 0.885; exogenous MOTS-c attenuated lung injury via ROS-CK2A-MYH9 signaling and antioxidant gene transcription in rats. PMID 40403491 Shen et al., Redox Biol 2025
  • MOTS-c plasma concentrations reduced in CPB patients with ALI; MOTS-c pretreatment alleviated LIRI via AMPK-HIF-1α-PFKFB3 glycolytic pathway in mice and cell models. PMID 40035775 Shen et al., Am J Respir Cell Mol Biol 2025
  • Circulating MOTS-c decreased in postoperative ALI patients; MOTS-c suppressed ferroptosis and alleviated MIR-induced ALI via PPARγ signaling in rats and MLE-12 cells. PMID 37290680 Lu et al., Eur J Pharmacol 2023
  • Engineered R13A-MOTS-c (5 mg/kg/day i.p. for 2 weeks) mitigated radiation-induced pulmonary inflammation and mitochondrial dysfunction via LAT1-mediated transport and Nrf2 activation in C57BL/6 mice. PMID 42142418 Zhang et al., Redox Biol 2026
  • MOTS-c content reduced in hyperoxia-induced BPD mice; exogenous MOTS-c alleviated alveolar simplification and pulmonary vascular abnormalities in Nrf2-dependent manner. PMID 41802484 Chen et al., Eur J Pharmacol 2026
  • MOTS-c levels lower in asthma patients vs. healthy volunteers; MOTS-c alleviated allergic asthma airway barrier dysfunction via Nrf2-dependent inhibition of epithelial apoptosis in HDM-stimulated mice and BEAS-2B cells. PMID 40472776 Zhang et al., Int Immunopharmacol 2025
• Non-alcoholic steatohepatitis (NASH) and liver injury Animal studies only
  • MOTS-c alleviated NASH-diet-induced liver steatosis, apoptosis, inflammation, and fibrosis in mice; interacts directly with BH3 domain of Bcl-2, increasing Bcl-2 stability. PMID 38206815 Lu et al., Cell Reports 2024
  • MOTS-c reduced APAP-induced liver injury in C57BL/6 mice via suppression of MAPK pathway (ERK, JNK, p38), reduced oxidative stress, inflammation, and apoptosis; MOTS-c levels reduced in AILI mice. PMID 41764620 Li et al., Protein Peptide Lett 2026
• Cancer (ovarian cancer, hepatocellular carcinoma, bone cancer pain, adrenal tumors) Mixed
  • MOTS-c levels reduced in serum and tumor tissues of ovarian cancer patients; exogenous MOTS-c inhibited OC cell proliferation, migration, invasion, and induced apoptosis in vitro and suppressed tumor growth in vivo via LARS1-USP7 ubiquitination axis. PMID 39321430 Yin et al., Adv Sci 2024
  • MOTS-c levels lower in HCC patient peripheral blood; MOTS-c promoted TRAIL-induced HCC cell apoptosis under hypoxia via MEF2A/DR4/DR5 axis. PMID 39581216 Shen et al., Exp Cell Res 2025
  • Endogenous MOTS-c lower in bone cancer pain mouse model; intraperitoneal MOTS-c robustly attenuated bone cancer-induced pain and bone destruction via AMPK-mediated mitochondrial biogenesis; chronic administration had little effect on liver, renal, lipid, or cardiac function in mice. PMID 38716540 Yang et al., Acta Biochim Biophys Sin 2024
  • MOTS-c mRNA decreased in all adrenal tumors vs. controls; serum MOTS-c protein increased in ACA and PCC but not ACC; MOTS-c protein expression declined with ACC stage progression. PMID 39201408 Kaminski et al., IJMS 2024
• Osteoporosis and bone metabolism In vitro only
  • MOTS-c (1.0 µM for 24 h or 0.5 µM for 48 h) increased osteoblast viability and promoted type I collagen synthesis (COL1A1, COL1A2) via TGF-β/SMAD signaling in hFOB1.19 cells. PMID 31081069 Che et al., Eur Rev Med Pharmacol Sci 2019
• Osteoarthritis and cartilage protection Animal studies only
  • Exogenous MOTS-c improved mitochondrial dysfunction, inhibited NLRP3 inflammasome, rescued chondrocyte pyroptosis, and delayed articular cartilage degeneration in a murine OA model via Nrf2/TXNIP/NLRP3 axis. PMID 41043625 Li et al., Free Radic Biol Med 2025
• Ischemic flap / soft tissue transplantation survival Animal studies only
  • MOTS-c improved blood perfusion, enhanced angiogenesis, reduced endothelial pyroptosis, enhanced autophagy, and attenuated lysosomal membrane permeabilization in ischemic flap mice via PLA2G4A-LMP axis. PMID 42153537 Shi et al., Autophagy 2026
• Intrauterine growth restriction (IUGR) / placental protection Animal studies only
  • MOTS-c (5 mg/kg) significantly attenuated hypoxia-induced IUGR by promoting placental angiogenesis and inhibiting oxidative stress in an Nrf2-dependent manner in mice. PMID 41268602 Chen et al., Int J Mol Med 2026
• Host defense / antibacterial activity Mixed
  • MOTS-c identified as a mitochondrial-encoded host defense peptide; targeted E. coli and MRSA membranes; fully neutralized MRSA infectivity in mouse acute peritonitis model; IFNγ and LPS induced endogenous MOTS-c expression in human monocytes; MOTS-c reprogrammed monocytes into macrophages with enhanced bacterial cleara PMID 42611943 Rice et al., eLife 2026
• Antiviral activity (hepatitis B virus infection) Mixed
  • MOTS-c negatively correlated with HBV DNA (R=-0.71); AUC 0.9530 for distinguishing CHB from healthy controls; 50-70% inhibition rate of HBV replication in vitro and in vivo; promotes mitochondrial biogenesis and MAVS signaling; no notable toxicity reported. PMID 37788894 Lin et al., Gut 2024
• Neurodegenerative diseases and ischemic stroke Human observational
  • Plasma MOTS-c decreased in Alzheimer's disease and acute ischemic stroke groups vs. controls; similar values in MS group vs. control. PMID 36303331 Sacmaci et al., J Biochem Mol Toxicol 2023
• Sarcopenia in peritoneal dialysis patients Human observational
  • PD patients with very high sarcopenia risk (SARC-F ≥2) had significantly lower serum MOTS-c and higher dialysate MOTS-c; serum MOTS-c directly correlated with muscle performance; ROC analysis supported diagnostic potential of MOTS-c for sarcopenia risk in PD patients. PMID 40005438 Zicarelli et al., Medicina 2025
• Pulmonary fibrosis Animal studies only
  • Review suggesting MOTS-c potential in pulmonary fibrosis based on its effects on glucose/lipid metabolism, mitochondrial homeostasis, and anti-inflammatory properties; no direct PF trial data presented. PMID 37307934 Zhang et al., Mitochondrion 2023
• Mesenchymal stem cell aging (in vitro) In vitro only
  • MOTS-c promoted homeostasis in aged human placenta-derived MSCs; activated AMPK, inhibited mTORC1, decreased ROS production and lipid synthesis in vitro. PMID 33639272 Yu et al., Mitochondrion 2021
• Skeletal muscle fiber composition and genetic variation (K14Q polymorphism) Human observational
  • East Asian-specific m.1382A>C polymorphism (K14Q) associated with higher MHC-IIx (fast-twitch fiber) proportion, higher peak torques of leg flexion/extension in men, and higher C allele frequency in sprint/power athletes vs. endurance athletes. PMID 34728329 Kumagai et al., BBA Gen Subj 2022

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.