Review
This review paper examines MOTS-c, a mitochondrial-derived microprotein (mitokine) encoded within the 12S rRNA gene, and its potential role in inflammatory lung diseases. The authors synthesize available experimental and clinical literature to explore how MOTS-c influences metabolic homeostasis, oxidative stress, inflammation, autophagy, cell death pathways (including apoptosis, ferroptosis, and pyroptosis), mitochondrial dysfunction, and immune responses. Key findings reported across the reviewed studies include: reduced circulating MOTS-c levels in various forms of acute respiratory distress; attenuation of lung injury following exogenous MOTS-c administration in preclinical models; a partial mechanistic link between remote ischemic preconditioning and MOTS-c release; decreased MOTS-c concentrations in chronic conditions such as COPD, obstructive sleep apnea, and asthma; and preliminary observations of elevated MOTS-c in lung cancer, tentatively attributed to NRF2-mediated antioxidant responses. The authors conclude that MOTS-c holds promise as both a biomarker and therapeutic candidate in respiratory medicine, while acknowledging that current evidence is largely preclinical and that well-designed translational and multicenter clinical trials are needed to confirm any clinical utility. Limitations include the heterogeneity of reviewed study designs and the early-stage, preliminary nature of much of the evidence.
Journal of translational medicine · Jun 2026DOI ↗ Animal only
This study investigated whether MOTS-c, a small peptide encoded within mitochondrial DNA, could protect the heart from ischemia-reperfusion (IR) injury. Using the Langendorff isolated heart perfusion model in female Wistar rats (n=6 per group), researchers subjected hearts to 30 minutes of global ischemia followed by 60 minutes of reperfusion. MOTS-c was administered either before ischemia or at the start of reperfusion. The study evaluated cardiac mechanical function, oxidative stress, mitochondrial enzyme activities, membrane potential, mitochondrial DNA (mtDNA) copy number, and regulatory gene expression across two distinct mitochondrial subpopulations — subsarcolemmal and interfibrillar mitochondria. IR injury significantly impaired cardiac recovery, increased oxidative stress, reduced electron transport chain activity, and decreased mtDNA copy number and regulatory gene expression. MOTS-c treatment was associated with improved post-ischemic mechanical recovery, reduced oxidative stress, partial preservation of mitochondrial enzyme activity and membrane potential, and attenuation of mtDNA loss. Protective effects were seen in both mitochondrial subpopulations, though the magnitude varied. Key limitations include the exclusive use of an isolated ex vivo animal model, small group sizes, a single sex, and uncharacterized signaling mechanisms underlying the observed effects.
Molecular biology reports · Jun 2026DOI ↗ Animal only
This study investigated whether the mitochondrial-derived peptide MOTS-c could improve survival of ischemic tissue flaps used in reconstructive surgery — a context where distal necrosis due to poor blood flow remains a significant clinical challenge. Using a rat ischemic flap model, researchers employed a broad range of techniques including RNA sequencing, tissue clearing, laser speckle contrast imaging, laser Doppler blood flow analysis, histological staining, Western blotting, ELISA, immunofluorescence, and adeno-associated virus (AAV)-mediated gene overexpression. The study also used human umbilical vein endothelial cells (HUVECs) for in vitro experiments. The authors report that MOTS-c treatment was associated with improved blood perfusion, enhanced angiogenesis, and better collagen remodeling in ischemic flaps. Mechanistically, the study found that MOTS-c appeared to suppress phosphorylation of PLA2G4A (cytosolic phospholipase A2) via the MAPK1/ERK2–MAPK3/ERK1–NF-κB signaling cascade, thereby reducing lysosomal membrane permeabilization (LMP), decreasing endothelial pyroptosis, and enhancing autophagy. AAV-mediated PLA2G4A overexpression in vivo was used to confirm this pathway. Key limitations include the absence of human clinical data and the complexity of the multi-modal experimental design, which makes it difficult to isolate individual mechanistic contributions.
Autophagy · Jun 2026DOI ↗ Animal only
This study investigated whether MOTS-c, a mitochondrial-derived peptide with metabolic and exercise-mimicking properties, could attenuate skeletal muscle loss in cancer cachexia. In vitro, differentiated myotubes treated with MOTS-c showed increased PGC-1α mRNA expression (~85%) and enhanced AMPK phosphorylation (~103%), suggesting activation of mitochondrial biogenesis and energy-sensing pathways. In vivo, male mice implanted with Colon-26 (C26) carcinoma cells developed significant systemic wasting (~9% body weight loss). Daily MOTS-c treatment did not prevent total body weight loss or fat mass loss in these tumor-bearing mice, but it did significantly preserve skeletal muscle mass — notably rescuing quadriceps weight (~12% vs. C26 vehicle controls). Mechanistically, MOTS-c appeared to modulate FOXO signaling and reduce atrogene expression (MuRF1 and Atrogin-1), key mediators of muscle protein breakdown, while promoting mitochondrial biogenesis markers. The authors conclude that MOTS-c partially protects against cachexia-associated muscle deterioration. Key limitations include the exclusive use of male mice, an animal-only in vivo model, and the authors' own acknowledgment that human studies are needed to validate these findings.
Frontiers in medicine · May 2026DOI ↗ Limited · human
This cross-sectional study investigated circulating levels of MOTS-c — a mitochondria-derived peptide involved in metabolic and immune regulation — in patients with Hashimoto's thyroiditis (HT) compared to healthy controls. A total of 180 participants (90 HT patients and 90 age- and sex-matched healthy controls) were enrolled. The study found that circulating MOTS-c levels were significantly lower in HT patients than in controls. Lower MOTS-c levels were independently associated with insulin resistance and markers of autoimmune burden (such as thyroid autoantibodies). The authors propose that impaired mitochondrial signaling, as reflected by reduced MOTS-c, may contribute to the pathophysiology of thyroid autoimmunity and metabolic dysregulation seen in HT. The study's cross-sectional design limits causal inference — it is unclear whether reduced MOTS-c is a cause or consequence of HT. Additional limitations include the single-timepoint measurement, potential confounders not fully addressed, and the absence of longitudinal follow-up. The findings position MOTS-c as a candidate biomarker linking metabolic dysfunction and immune dysregulation in thyroid autoimmunity, though further prospective and mechanistic research is needed to confirm this relationship.
Journal of clinical medicine · May 2026DOI ↗ Limited · human
This observational cohort study measured serum levels of two circulating peptides — Nardilysin (NRDc) and MOTS-c — in 150 participants (118 kidney transplant recipients [KTRs] and 32 age-matched controls) to explore their potential roles as cardiometabolic biomarkers in this high-risk population. Using commercial ELISA kits, the researchers found that median serum NRDc and MOTS-c levels were significantly higher in KTRs compared to controls. Penalized logistic regression revealed an inverse association between elevated NRDc levels and prevalent cardiovascular (CV) disease in KTRs, suggesting that higher NRDc may be associated with lower odds of existing CV disease. KTRs were followed for a median of approximately 29 months, during which renal allograft loss and all-cause mortality were analyzed using Fine-Gray competing risk regression. The authors propose that elevated NRDc and MOTS-c in KTRs may reflect altered metabolic and inflammatory pathways unique to this population. Key limitations include the observational design, the relatively small and single-center cohort, the cross-sectional nature of the CV disease association, and the lack of incident CV event data. The authors acknowledge that longitudinal studies are needed to clarify causal relationships.
Kidney & blood pressure research · May 2026DOI ↗ Limited · human
This pilot observational study investigated the relationship between MOTS-c — a mitochondria-derived peptide — and cardiovascular risk markers in 32 stable peritoneal dialysis (PD) patients (mean age ~61 years, ~63% male). Researchers measured MOTS-c in three compartments: serum, urine, and peritoneal dialysate. Oxidative stress was assessed via plasma Advanced Oxidation Protein Products (AOPPs), and vascular stiffness was evaluated using carotid-femoral Pulse Wave Velocity (PWV), with echocardiography used to assess left ventricular systolic function. The study found that urinary MOTS-c was inversely correlated with AOPPs (suggesting a link to lower oxidative stress) and positively associated with PWV and left ventricular systolic function. Dialysate MOTS-c showed a strong inverse correlation with PWV and with both systolic and diastolic blood pressure, suggesting an association with a more favorable vascular profile. The authors propose a novel "Mitochondrial-Vascular Axis" in uremia and position MOTS-c as a potential biomarker. Key limitations include the very small sample size (n=32), pilot/cross-sectional design, single-center recruitment, and inability to establish causality from correlational data.
International urology and nephrology · May 2026DOI ↗ Animal only
This study investigated whether the mitochondrial-derived peptide MOTS-c could protect the neonatal heart from hyperoxia-induced injury. Using neonatal mice exposed to 85% oxygen as an in vivo model and the rat cardiomyocyte cell line H9C2 as an in vitro model, researchers found that hyperoxia caused cardiac hypertrophy, fibrosis, and dysfunction, alongside reduced circulating MOTS-c levels. Administration of MOTS-c was reported to markedly reduce these pathological changes and restore cardiac function in the mouse model. Mechanistically, the study found that hyperoxia activates a KEAP1–PGAM5–AIFM1 signaling axis, triggering a ROS-specific form of programmed cell death called oxeiptosis. MOTS-c appeared to interact directly with KEAP1, preserving its binding to PGAM5 and thereby preventing nuclear translocation of AIFM1, the downstream executioner of oxeiptosis. Overexpression of KEAP1 abolished MOTS-c's protective effects, supporting KEAP1 as a key target. Limitations include exclusive reliance on animal and cell-line models with no human data, a relatively narrow mechanistic focus, and the absence of long-term outcome measures. These findings are preclinical and require validation in human studies before clinical conclusions can be drawn.
Life sciences · May 2026DOI ↗ Animal only
This study investigated an engineered variant of the mitochondria-derived peptide MOTS-c, called R13A-MOTS-c, designed to overcome the poor cellular permeability of the wild-type peptide. The researchers substituted arginine at position 13 with alanine to increase hydrophobicity, then characterized the modified peptide's uptake mechanism, showing through competition assays and knockdown experiments that it enters cells via the LAT1 amino acid transporter. In vitro, R13A-MOTS-c was reported to reduce inflammatory markers, oxidative damage, and mitochondrial dysfunction in mouse lung epithelial (MLE-12) cells exposed to radiation. In vivo, C57BL/6 mice receiving thoracic irradiation (20 Gy) and treated with intraperitoneal R13A-MOTS-c showed attenuated pulmonary inflammation, oxidative stress, and mitochondrial impairment compared to controls. The proposed mechanism centers on Nrf2 pathway activation, supported by evidence of increased nuclear Nrf2 translocation and upregulation of downstream target genes; protective effects were lost when LAT1 or Nrf2 was inhibited or knocked out. Key limitations include exclusive use of animal and cell models with no human data, a single radiation dose and treatment regimen tested, and the need for further pharmacokinetic and safety characterization before clinical translation.
Redox biology · May 2026DOI ↗ Limited · human
This study investigated the role of two mitochondrial-derived peptides (MDPs) — humanin (HN) and MOTS-c — in atrial fibrillation (AF), a common heart rhythm disorder. Researchers first examined human atrial tissue using public gene expression data, immunohistochemistry, and immunofluorescence, and measured plasma levels in a matched cohort of 39 AF patients and 39 sinus rhythm controls. They found that both peptides were significantly downregulated in AF tissue, with levels inversely correlated with fibrosis extent. Plasma MOTS-c was also reduced in AF patients and inversely correlated with NT-proBNP, a heart stress biomarker. Using an angiotensin II (AngII)-induced mouse AF model (n=36, male C57BL/6J), the study found that treatment with HNG (an HN analogue) or MOTS-c reduced AF inducibility and attenuated atrial fibrosis and hypertrophy. Peptide treatment was associated with improved mitochondrial structure, reduced fission proteins (Drp1, Fis1), and lower inflammatory cytokines. In vitro experiments in rat cardiomyocytes and fibroblasts showed reduced oxidative stress, fibroblast activation, proliferation, and migration. Exploratory RNA-sequencing suggested distinct mechanistic pathways. Key limitations include the small human cohort, the use of an animal model that may not fully replicate clinical AF, and the exploratory nature of mechanistic findings.
Biomedicines · May 2026DOI ↗ Limited · human
This cross-sectional study investigated the relationship between serum levels of MOTS-c — a mitochondria-derived peptide encoded in the 12S rRNA — and myocardial ischemia-reperfusion injury (MIRI) in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI). Seventy-two AMI patients were divided into MIRI (n=34) and non-MIRI (n=38) groups. The study measured MOTS-c concentrations in both peripheral serum and intracoronary blood, alongside clinical variables. The MIRI group displayed lower systolic blood pressure, lower pre-operative TIMI grade, and lower HDL-C, while showing higher total ischemic time, door-to-balloon time, culprit vessel stenosis severity, Killip grade, and adverse event rates. Multivariate logistic regression identified postoperative peripheral serum MOTS-c as an independent protective factor against MIRI, and ROC analysis suggested potential predictive value for MIRI. Limitations include the small sample size, single-center cross-sectional design, lack of causal inference, and the absence of dynamic longitudinal monitoring of MOTS-c. The authors conclude that MOTS-c warrants further investigation as a novel biomarker and potential therapeutic target for MIRI, pending validation in larger prospective studies.
Biomedicines · Apr 2026DOI ↗ Review
This narrative review examines the pharmacological mechanisms, safety profiles, and regulatory status of twelve peptides commonly marketed in sports medicine contexts, spanning both FDA-approved compounds (e.g., tesamorelin/Egrifta) and unapproved "gray market" substances (e.g., BPC-157, CJC-1295, TB-500, ipamorelin, and others). The authors note that while many unapproved peptides show promising tissue repair and metabolic effects in animal models, rigorous human safety and efficacy data are largely absent. The review highlights a growing direct-to-consumer gray market operating outside regulatory oversight and discusses the potential for serious patient harm. Notably, the authors address the placebo effect as a possible mediator of perceived peptide efficacy and examine how social media may amplify this effect. A clinician-oriented framework is proposed to guide evidence-based patient discussions about peptide use for musculoskeletal healing and athletic performance, including consideration of alternative treatments. Key limitations include the narrative (non-systematic) review methodology and the inherently limited and heterogeneous evidence base for most compounds discussed, particularly in human populations.
Sports medicine (Auckland, N.Z.) · Apr 2026DOI ↗ Limited · human
This observational case-control study investigated whether serum MOTS-c levels and the mitochondrial m.1382A>C gene polymorphism are associated with polycystic ovary syndrome (PCOS) in adolescents. A total of 246 participants aged 12–18 were enrolled: 121 diagnosed with PCOS (based on irregular menstrual cycles and clinical/biochemical hyperandrogenism) and 125 healthy controls with regular menstruation. Serum MOTS-c levels were measured by ELISA, and the m.1382A>C polymorphism was assessed by gene sequencing. The study found that mean serum MOTS-c levels were slightly higher in the PCOS group compared to controls, but this difference did not reach statistical significance (p = 0.059). No significant associations were observed between MOTS-c levels and anthropometric or metabolic parameters within the PCOS group. Notably, all participants carried the wild-type (A/A) genotype for the m.1382A>C polymorphism, making genetic association analysis impossible in this cohort. The authors concluded that MOTS-c may play only a minor role in PCOS pathophysiology. Limitations include the modest sample size, the adolescent-only population, the absence of polymorphism variability, and the cross-sectional design precluding causal inference.
Archives of endocrinology and metabolism · Apr 2026DOI ↗ ReviewPreprint
This narrative review examines the pharmacological mechanisms, safety profiles, and regulatory status of twelve peptides commonly encountered in sports medicine and athletic performance contexts, including both approved agents (e.g., tesamorelin/Egrifta, sermorelin) and unapproved "gray market" compounds (e.g., BPC-157, CJC-1295, TB-500, ipamorelin, AOD-9604, FS-344, GHK-Cu, MOTS-C, SS-31, and thymosin beta-4). The authors note that while many unapproved peptides show promising tissue repair and metabolic outcomes in animal models, rigorous human safety and efficacy data remain scarce. The review highlights the emergence of a direct-to-consumer gray market operating outside regulatory oversight and the potential for serious patient harm. It further discusses the placebo effect as a potential mediator of perceived peptide efficacy, and how social media may amplify this effect. The authors provide a clinical framework to guide patient-provider discussions and promote evidence-based practice for musculoskeletal healing. Key limitations include the narrative (non-systematic) review design, reliance on preclinical literature for most unapproved compounds, and the absence of head-to-head human trials for the majority of agents discussed.
Unknown journal · Apr 2026DOI ↗ Limited · human
This study investigated the role of MOTS-c, a mitochondrially encoded regulatory peptide, in protecting spermatogenesis. Researchers first measured serum MOTS-c levels in patients with oligoasthenozoospermia (a condition involving reduced and poorly motile sperm), finding these levels were significantly lower than in fertile controls and correlated positively with semen quality parameters. To model spermatogenic dysfunction mechanistically, the researchers used a microgravity-based mechanical stress model in mice, which induced decreased sperm concentration, disrupted seminiferous tubule architecture, and reduced spermatogonia counts. Exogenous MOTS-c administration was shown to ameliorate these impairments by suppressing oxidative stress and ferroptosis — a form of iron-dependent programmed cell death. The study identified SLC7A11 (Solute Carrier Family 7 Member 11), a known ferroptosis regulator, as a molecular target of MOTS-c. Loss- and gain-of-function experiments confirmed that SLC7A11 inhibits ferroptosis and oxidative stress while promoting spermatogonia proliferation. MOTS-c's protective effects were shown to depend, at least in part, on upregulating SLC7A11 under mechanical stress conditions. Limitations include the small and uncharacterized human cohort, reliance on an indirect mechanical stress model, and predominantly animal/cellular mechanistic data.
Free radical biology & medicine · Mar 2026DOI ↗ Animal only
This animal study investigated whether MOTS-c, a 16-amino acid mitochondrial-derived peptide, influences adrenal gland physiology in adult male Wistar rats. Sixteen rats received either continuous subcutaneous MOTS-c or saline for 24 hours via micro-osmotic pumps. The researchers used qRT-PCR, immunohistochemistry, ELISA, and RNA sequencing to assess adrenal tissue responses. The study first confirmed that endogenous MOTS-c expression was higher in the zona fasciculata/reticularis compared to the zona glomerulosa. MOTS-c treatment did not alter classical steroidogenic gene expression or circulating corticosterone and aldosterone levels. However, RNA sequencing identified 39 differentially expressed genes, most notably a 4.3-fold upregulation of the purinergic receptor P2ry4. The authors interpreted these findings as evidence that MOTS-c "primes" adrenocortical cells for steroidogenic responsiveness—via calcium signaling, lipid metabolism modulation, stress-response protein downregulation, and mitophagy inhibition—without directly stimulating basal hormone synthesis. Key limitations include the exclusive use of male rats, the short 24-hour treatment window, small sample size (n=16), and the absence of functional stimulation challenges (e.g., ACTH) to test the proposed "readiness" hypothesis.
Folia histochemica et cytobiologica · Mar 2026DOI ↗ Animal only
This study examined the effects of graviola (Annona muricata L.) oil extract (GOE) supplemented at three doses (200, 400, and 600 mg/kg feed) on growth performance and circadian rhythm profiles of several biomarkers in 48 male Anatolian Merino lambs over a 60-day feeding trial. Blood samples were collected at four time points across the day (07:00, 13:00, 19:00, and 01:00) on multiple study days to capture circadian variation. Measured biomarkers included Apelin (an adipokine), cardiac troponin I (cTnI), the circadian clock protein BMAL1, the mitochondria-derived peptide MOTS-c, and brown adipose mitochondrial carrier protein 1 (BMCP1), all assessed via ELISA. The 400 mg/kg dose was associated with the greatest linear improvement in live weight gain and with modulation of BMAL1, MOTS-c, and BMCP1 peaking at 19:00. The 600 mg/kg dose showed the most favorable results for Apelin and cTnI at certain time points. Limitations include the exclusive use of a single animal species, a relatively small sample size, lack of human relevance, and the observational nature of biomarker interpretation within a non-randomized animal production context.
BMC veterinary research · Mar 2026DOI ↗ Limited · human
This observational study investigated circulating levels of MOTS-c — a mitochondrial-derived peptide involved in metabolic regulation — in adults with and without obesity, and examined whether levels changed after bariatric surgery. Researchers compared 22 lean controls with 32 obese participants scheduled for bariatric surgery, measuring MOTS-c concentrations alongside metabolic and inflammatory markers. A subset of 10 obese patients was followed longitudinally before and 6 months after surgery. Adipose tissue MOTS-c expression was also assessed via immunofluorescence in lean (n=6) and obese (n=14) subjects. The study found that circulating MOTS-c was significantly higher in obese versus lean individuals (273 vs. 223 pg/mL), and positively correlated with BMI and HOMA-IR. A notable biphasic relationship emerged between MOTS-c and HOMA-IR, with a sharp rise above a threshold of ~6.6 mmol/L×µU/mL. Despite significant weight and BMI reductions following bariatric surgery, MOTS-c levels did not change significantly post-operatively. Adipose tissue expression did not differ between groups. The authors suggest MOTS-c may reflect a compensatory metabolic response in obesity and insulin resistance. Key limitations include the small sample size, particularly in the longitudinal substudy, and the lack of an independent validation cohort.
Journal of clinical & translational endocrinology · Dec 2025DOI ↗ ReviewPreprint
This review paper examines the pharmacological mechanisms, safety profiles, and regulatory status of both approved and unapproved peptide therapies relevant to sports medicine, musculoskeletal injury recovery, and athletic performance enhancement. The compounds reviewed span a wide spectrum — from FDA-approved agents such as tesamorelin and sermorelin, to gray-market compounds including BPC-157, TB-500, CJC-1295, Ipamorelin, AOD-9604, FS-344, GHK-Cu, MOTS-C, and SS-31. The authors note that while many unapproved peptides show promising results in preclinical and animal models — including favorable tissue repair and metabolic effects — rigorous human safety and efficacy data remain scarce. The review highlights a growing direct-to-consumer gray market operating outside regulatory oversight and discusses how social media may amplify perceived benefits through placebo-related mechanisms. The paper also offers a clinical framework to guide patient conversations and support evidence-based decision-making. Key limitations include the inherent constraints of a narrative review design, reliance on heterogeneous preclinical data for unapproved compounds, and the absence of controlled human trials for most of the highlighted peptides.
Unknown journal · Dec 2025DOI ↗