Overview
MOTS-c is a naturally occurring peptide encoded within the mitochondrial genome, specifically derived from the 12S ribosomal RNA sequence, making it part of a relatively recently discovered class of molecules known as mitochondrial-derived peptides (MDPs). Unlike most peptides, which are encoded by nuclear DNA, MOTS-c originates from within the mitochondria themselves, the energy-producing structures found in nearly all human cells. It is a short peptide consisting of 17 amino acids and has drawn considerable scientific interest for its apparent roles in cellular energy regulation, oxidative stress responses, and mitochondrial function. Researchers have investigated MOTS-c in a variety of preclinical and laboratory settings, including studies related to tissue survival, oxidative stress, and cellular protection mechanisms. MOTS-c is intended strictly for research purposes and is not approved for human use or consumption.
Research & Bioactivity
MOTS-c is a mitochondrial-derived peptide encoded by a mitochondrial ribosomal RNA open reading frame, and researchers have studied it extensively in relation to cellular energy regulation, oxidative stress, and metabolic homeostasis. Studies have examined its role in mitochondrial function, particularly its capacity to influence reactive oxygen species production and mitochondrial membrane stability in both in vitro and animal model settings. Research has investigated MOTS-c in the context of cardiovascular biology, including studies exploring its association with myocardial ischemia-reperfusion injury in clinical cross-sectional research and its potential cardioprotective properties in neonatal hyperoxia models. Researchers have also studied MOTS-c in relation to vascular function and oxidative stress markers in peritoneal dialysis patient populations, as well as in models of radiation-induced tissue injury, where engineered analogs have been explored to improve cellular delivery. Additional research has examined MOTS-c in the context of surgical tissue transplantation, looking at how it may relate to lysosomal membrane integrity and cellular survival under ischemic conditions.
Published Research
MOTS-c, a mitochondrial-derived peptide, ameliorates lysosomal membrane permeability and improves survival of soft tissue transplantation.
Shi J, Wu Y, Liu X, Xia W, Wu J, et al. — 2026
Distal ischemic necrosis remains a major challenge in reconstructive surgery. Mitochondria and lysosomes interact via signaling and membrane contacts to maintain cellular homeostasis. Mitochondrial-derived peptide MOTS-c, encoded by the rRNA open reading frame, enhances mitochondrial function by reducing reactive oxygen species (ROS) and stabilizing the membrane potential, potentially preserving lysosomal integrity and reducing lysosomal membrane permeabilization (LMP). This study investigated the protective effects and underlying mechanisms of MOTS-c in ischemic flaps. RNA sequencing explored MOTS-c mechanisms in ischemic flaps. Tissue clearing, laser speckle contrast imaging and Doppler analyses revealed improved blood flow perfusion following MOTS-c treatment. Histological staining (HE, Masson, F-CHP) demonstrated enhanced angiogenesis and collagen remodeling. Western blotting, ELISA, and immunofluorescence were used to assess pyroptosis, macroautophagy/autophagy, LMP, and MAPK1/ERK2-MAPK3/ERK1-NFKB/NF-κB pathway-related proteins. MOTS-c reduced endothelial pyroptosis, enhanced autophagy, and attenuated LMP in ischemic flaps. Mechanistically, overexpression of PLA2G4A/cPLA2 (phospholipase A2, group IVA (calcium, calcium dependent)) via AAV confirmed that MOTS-c enhances autophagy and reduces pyroptosis and LMP by suppressing PLA2G4A phosphorylation. Furthermore, MOTS-c inhibited PLA2G4A via the MAPK1-MAPK3-NFKB signaling cascade, thereby reducing LMP and enhancing flap survival. These findings suggest that MOTS-c restores cellular homeostasis by targeting the PLA2G4A-LMP axis, representing a promising therapeutic strategy for improving outcomes in ischemic flap surgery.
LAT1-mediated delivery of engineered R13A-MOTS-c attenuates radiation-induced lung injury via Nrf2 activation and mitochondrial protection.
Zhang YL, Huang G, Li SP, Zhang WL, Chen D, et al. — 2026
MOTS-c exhibits substantial antioxidant and anti-inflammatory properties, yet its therapeutic potential is constrained by poor membrane permeability due to its high polarity. To overcome this limitation, we engineered R13A-MOTS-c by substituting the polar arginine at position 13 with alanine in the wild-type peptide (Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg). This modification increased the peptide's hydrophobicity index from -0.938 to -0.544, measurably improving its cellular uptake. Functional uptake assays, including competition with canonical LAT1 substrates (leucine, BCH) and LAT1 knockdown experiments, further confirmed that R13A-MOTS-c enters cells via LAT1-mediated transport. In vitro experiments revealed that R13A-MOTS-c suppressed inflammatory responses, oxidative damage, and mitochondrial impairment in MLE-12 cells. In vivo studies demonstrated that daily intraperitoneal administration of R13A-MOTS-c (5 mg/kg for 2 weeks) effectively mitigated radiation-induced pulmonary inflammation, oxidative stress, and mitochondrial dysfunction in C57BL/6 mice exposed to 20 Gy thoracic irradiation. Mechanistically, R13A-MOTS-c activated the Nrf2 signaling pathway, as evidenced by increased nuclear translocation of Nrf2 and upregulation of its downstream targets gene. These effects were abolished upon LAT1 inhibition, Nrf2 inhibition, or in Nrf2-knockout conditions. Collectively, these findings indicate that LAT1-mediated uptake of R13A-MOTS-c alleviates radiation-induced lung injury through Nrf2 pathway activation and mitochondrial function restoration, offering a promising therapeutic strategy for clinical applications.
MOTS-c attenuates hyperoxia-induced neonatal cardiac injury by inhibiting oxeiptosis via maintaining the KEAP1-PGAM5 interaction.
Li SH, Chen SQ, Lu T, Wang JH, Wang JX, et al. — 2026
AIMS: Hyperoxia-induced oxidative stress is a primary cause of neonatal injury. Neonatal heart shows a particular susceptibility to hyperoxic toxicity, yet mechanisms and effective therapeutic strategies remain limited. Oxeiptosis is a ROS-specific programmed cell death. Mitochondrial-derived peptide MOTS-c possesses well-known anti-oxidative effect. This study investigated the cardio-protective role of MOTS-c in hyperoxia exposed neonatal mice and its mechanism. MAIN METHODS: Neonatal mice exposed hyperoxia (85% O) were used to establish the hyperoxic cardiac injury model. Additionally, the rat cardiomyocyte cell line H9C2 were subjected to hyperoxic conditions as an in vitro model. Serum MOTS-c content was measured using enzyme-linked immunosorbent assay. Hematoxylin and eosin staining, Real-time PCR, Western blotting, immunohistochemistry, and immunofluorescence techniques were employed to evaluate the effects of MOTS-c on hyperoxia-induced cardiac insufficiency. KEY FINDINGS: We found that hyperoxia exposure in neonatal mice led to significant cardiac hypertrophy, fibrosis, and dysfunction, concomitant with decreased serum MOTS-c content. Administration of MOTS-c markedly ameliorated these pathological changes and restored cardiac function. In vitro and in vivo experiments revealed that hyperoxia triggers oxidative stress and oxeiptosis via activating KEAP1-PGAM5-AIFM1 axis, and MOTS-c inhibited oxeiptosis. Mechanistically, MOTS-c could potentially interact with KEAP1, thereby maintaining the KEAP1-PGAM5 interaction, and inhibiting the downstream nuclear translocation of AIFM1. Notably, KEAP1 overexpression abrogated the protective effects of MOTS-c, confirming KEAP1 as a critical target of MOTS-c in hyperoxia-induced cardiac injury. SIGNIFICANCE: MOTS-c attenuates hyperoxic cardiac injury by inhibiting KEAP1-mediated oxeiptosis, highlighting its potential as a novel therapeutic agent for neonatal cardiomyopathy.
MOTS-c is associated with oxidative stress and arterial stiffness in peritoneal dialysis patients: a pilot study.
Musolino M, Roumeliotis A, Roumeliotis S, Zicarelli M, Ruosi F, et al. — 2026
PURPOSE: Oxidative stress (OS) and endothelial dysfunction are major drivers of cardiovascular disease (CVD) in peritoneal dialysis (PD). MOTS-c, a mitochondria-derived peptide, is emerging as a key regulator of skeletal muscle health, metabolic homeostasis, and vascular function, yet its role in the uremic environment remains unexplored. We investigated the relationship between MOTS-c levels, OS markers, and vascular stiffness in PD patients. METHODS: This pilot, clinical study included 32 stable PD patients (mean age 60.7 ± 1.2 years, 62.5% male). MOTS-c levels were quantified in serum (sMOTS-c), urine (uMOTS-c), and peritoneal dialysate (dMOTS-c). Systemic oxidative status was assessed via plasma Advanced Oxidation Protein Products (AOPPs). Vascular function was evaluated by carotid-femoral Pulse Wave Velocity (PWV), and left ventricular systolic function was assessed echocardiographically. RESULTS: Urinary MOTS-c (uMOTS-c) levels were inversely correlated with serum AOPPs (R = - 0.592, p = 0.012) and a positive association with PWV (R = 0.708, p = 0.001) and left ventricular systolic function (R = 0.440, p = 0.04). Conversely, dialysate MOTS-c (dMOTS-c) were strongly and inversely correlated with PWV (R = - 0.717, p = 0.019) as well as systolic and diastolic blood pressure (R = -0.5, p < 0.01). CONCLUSION: Ηigher urinary MOTS-c was linked to lower systemic oxidative stress, suggesting a potential protective role, and associated with greater arterial stiffness, potentially reflecting a compensatory response to vascular injury. In contrast, higher peritoneal MOTS-c levels were associated with an improved vascular profile. These findings suggest a novel 'Mitochondrial-Vascular Axis' in uremia, highlighting MOTS-c as a potential biomarker.
The Association Between Serum MOTS-c Levels and Myocardial Ischemia-Reperfusion Injury in Patients with Acute Myocardial Infarction: A Cross-Sectional Study.
Peng L, Li Y, Duan X, Long J, Ran Q, et al. — 2026
: Percutaneous coronary intervention (PCI) effectively restores coronary flow in acute myocardial infarction (AMI), but myocardial ischemia-reperfusion injury (MIRI) remains a major prognostic determinant. Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) has shown cardiovascular protective effects, yet its association with MIRI is unclear. This study aimed to investigate the relationship between serum MOTS-c levels and MIRI in AMI patients. : Seventy-two AMI patients undergoing PCI were enrolled and divided into MIRI ( = 34) and non-MIRI ( = 38) groups. Clinical data and MOTS-c levels in peripheral serum and intracoronary blood were compared. Multivariate logistic regression and receiver operating characteristic (ROC) analysis were performed to identify MIRI predictors. : The MIRI group exhibited lower systolic blood pressure, preoperative thrombolysis in myocardial infarction (TIMI) grade, and HDL-C, but higher total ischemic time, door-to-balloon time, culprit vessel stenosis severity, Killip grade and adverse event incidence (all < 0.05). Postoperative peripheral serum MOTS-c levels were significantly lower in the MIRI group than in the non-MIRI group ( < 0.05), while preoperative peripheral and intracoronary MOTS-c levels showed no significant differences between groups. Multivariate logistic regression identified postoperative peripheral MOTS-c levels (OR = 0.986, 95%CI: 0.976-0.996) and preoperative TIMI grade ≥ 1 (OR = 0.036, 95%CI: 0.004-0.309) as independent protective factors for MIRI, whereas serum creatinine was identified as an independent risk factor. ROC analysis demonstrated that postoperative peripheral MOTS-c levels predicted MIRI with an area under the curve of 0.648. : Postoperative peripheral serum MOTS-c levels represent an independent protective factor against MIRI in patients with acute myocardial infarction and suggest a potential predictive value for MIRI, although its clinical utility as a standalone predictor requires further validation through dynamic monitoring and larger-scale studies. This finding may offer a potential novel biomarker and therapeutic direction for MIRI.