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Mtc2.5
MOTS-c Research
Mostly mechanism / observational
19 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most MOTS-c studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from medium-quality meta-analyses and randomised trials published 2015–2026 with a typical study size of 602 participants.
Based on 19 studies · 1 meta-analysis · 1 RCT · 723 total participants
Confidence
Moderate confidence
By outcome
Longevity & agingA mitochondrial-derived peptide with exercise-mimetic and metabolic effects in animals plus observational human associations; no interventional human evidence. · Not established (no interventional human data)
Mostly mechanism / observational10 studies
Glucose & metabolicImproved insulin sensitivity/glucose metabolism in animals only; human data are observational, not interventional. · Not established (no interventional human data)
Mostly mechanism / observational6 studies
Exercise & physical performance
Mostly mechanism / observational3 studies
Active research area
11 studies in the last 5 years · Latest meta-analysis: 2024
201520202026
1Review2026
In plain English: The increasingly recognized role of MDPs in nonpulmonary diseases sheds light on the importance of more investigations of MDPs, their clinical and mechanistic roles, and their therapeutic potential for pulmonary diseases.
Behan M, Yen K, Cohen P, Kliment CR. · American journal of physiology. Lung cellular and molecular physiology (2026)
MDPs have been shown to be altered in a number of disease states and have mitochondrial, nuclear, and extracellular actions.
Most published work on MDPs has focused on MOTS-c and Humanin's actions in tissues with high mitochondrial density (heart, skeletal muscle, and brain) or in disease states of advanced age-Alzheimer's, cancer, and cardiovascular disease.
This review aims to highlight the existing gaps in knowledge related to MDPs' role in lung homeostasis and disease-including acute lung injury, chronic obstructive pulmonary disease, allergic asthma, and pulmonary fibrosis.
In plain English: Our results indicate that repeated heat stress specifically modulates the levels of the mitokines MOTS-c and FGF21 in a manner that is comparable to, but not identical to, exercise.
Elhusseiny R, Ihsan M, Labidi M, Alhammoud M, Mtibaa K, Nader N, Nasir N, Farooq A, Papakostas E, Olory B, Cruz F, D'Hooghe P, Racinais S, Deldicque L. · Medicine and science in sports and exercise (2025)
Results Although immobilization did not induce any effect on mitokine levels, repeated heat treatment upregulated the circulating MOTS-c ( P = 0.033) and downregulated the skeletal muscle FGF21 ( P = 0.027) levels.
Immobilization decreased muscle thickness ( P = 0.012, η2 = 0.32) and cross-sectional area ( P < 0.01, η2 = 0.75) of the gastrocnemius medialis.
Conclusions Our results indicate that repeated heat stress specifically modulates the levels of the mitokines MOTS-c and FGF21 in a manner that is comparable to, but not identical to, exercise.
In plain English: Beyond summarising its multifaceted roles, this review also uniquely compiles and discusses the distinct exogenous MOTS-c therapeutic approaches, including varying doses and dosing schedules, applied in preclinical metabolic disease studies, thereby providing valuable insights into future translational research.
Fang T, Han JC, Taberner A, Pham T. · Life sciences (2025)
Emerging evidence suggests that insufficient MOTS-c production from dysfunctional mitochondria contributes to the pathological development of diabetes and its complications through its regulatory effects on cellular retrograde signalling.
This review systematically classifies and analyses the various associations of MOTS-c with T2DM risk factors and summarises the relevant changes in a novel tabular format.
In addition, the key role of MOTS-c in the major diabetes-related complications is specifically explored, with a special focus on its protective and therapeutic potential in diabetic cardiomyopathy.
In plain English: This framework positions mitokine signaling at the interface between mitochondrial dysfunction, systemic stress adaptation, and cardiovascular disease while identifying mechanistic and translational questions requiring prospective validation.
Kurian GA. · Journal of bioenergetics and biomembranes (2026)
Importantly, such associations do not establish that sustained mitokine signaling is itself maladaptive, and major mechanistic uncertainties remain, particularly for mitochondrial-derived peptides.
We integrate these observations within a proposed "mitokine code" framework in which mitokine identity, relative patterns, temporal dynamics, and disease context may collectively provide information about mitochondrial stress and systemic adaptation.
We further evaluate the potential and current limitations of mitokines as cardiovascular biomarkers and therapeutic targets.
In plain English: Current evidence positions MOTS-c as a promising biomarker and potential therapeutic candidate in respiratory medicine.
Amado CA, Agüero J, García-Unzueta M, Berja A, Lavín BA, Martín-Audera P. · Journal of translational medicine (2026)
In contrast, chronic respiratory diseases such as chronic obstructive pulmonary disease, obstructive sleep apnea, and asthma are characterized by decreased MOTS-c concentrations, reflecting severe mitochondrial dysfunction and reduced cytoprotective capacity.
Preliminary observations suggest increased MOTS-c levels in lung cancer, potentially related to NRF2-mediated antioxidant responses, although these findings require further validation.
Conclusions Current evidence positions MOTS-c as a promising biomarker and potential therapeutic candidate in respiratory medicine.
In plain English: Therefore, further research, particularly controlled clinical trials and longitudinal studies, is needed to confirm these findings and evaluate MDP's potential as a therapeutic target in the prevention and management of metabolic diseases.
Ayubi N, Wibawa JC, Kurnaz M, Komaini A. · Physiology international (2026)
However, these findings should be interpreted with caution due to the limited number of studies and variations in study design, subject characteristics, and exercise protocols.
Conclusion Available evidence suggests that physical exercise has the potential to increase MDP levels, which may be associated with improved metabolic function, increased insulin sensitivity, and the efficiency of cellular energy metabolism.
However, current evidence is limited, particularly in human studies.
In plain English: Its primary target organ appears to be the skeletal muscle, and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation.
Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J. · Cell Metab (2015)
Discovery paper: identifies MOTS-c, a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA, that regulates insulin sensitivity and metabolic homeostasis
Cellular action is inhibition of the folate cycle and de novo purine biosynthesis, leading to AMPK activation, with skeletal muscle as the primary target
MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity
In plain English: Mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice... In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation.
Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D. · Nat Commun (2021)
In mice, MOTS-c treatment enhanced physical performance in young, middle-aged and old animals, and intermittent dosing (3 times a week) started late in life increased physical capacity and healthspan.
MOTS-c regulated nuclear genes related to metabolism and proteostasis and modulated skeletal-muscle metabolism and myoblast stress adaptation.
The human part is observational: exercise raised the body's own MOTS-c in skeletal muscle and in circulation. No person was given MOTS-c.
In plain English: MOTS-c... translocates to the nucleus and regulates nuclear gene expression following metabolic stress in a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent manner.
Kim KH, Son JM, Benayoun BA, Lee C. · Cell Metab (2018)
Mechanistic cell study showing MOTS-c translocates to the nucleus and regulates nuclear gene expression in an AMPK-dependent manner under metabolic stress
Under glucose restriction, MOTS-c regulated genes with antioxidant response elements (ARE) and interacted with the stress transcription factor NRF2 (NFE2L2)
Frames a bi-genomic 'mitonuclear' communication mechanism — a mitochondrial-encoded factor controlling the nuclear genome
In plain English: Circulating MOTS-c level was significantly reduced in diabetic individuals but was increased significantly in obesity patients.
Zhou Q, Yin S, Lei X, Tian Y, Lin D, Wang L, Chen Q. · Diabetol Metab Syndr (2024)
Systematic review and meta-analysis of 6 case-control studies and 1 cross-sectional study (11 groups, 602 participants) on circulating MOTS-c across metabolic states.
Pooled over diabetes and obesity together, plasma MOTS-c was lower (SMD -0.37, 95% CI -0.53 to -0.20). In subgroups it was lower in type 2 diabetes (SMD -0.89) and higher in obesity once overweight people were excluded (SMD 0.51).
MOTS-c correlated positively with total cholesterol (r = 0.29) and LDL-c (r = 0.30).
In plain English: MOTS-c may act as an inhibitor of VC by activating the AMPK signaling pathway and suppressing the expression of the AT-1 and ET-B receptors.
Wei M, Gan L, Liu Z, Liu L, Chang JR, Yin DC. · Cardiorenal Med (2020)
Rat model of vascular calcification induced by vitamin D3 and nicotine, MOTS-c injected at 5 mg/kg a day for 4 weeks.
MOTS-c treatment significantly attenuated vascular calcification. The abstract reports no myocardial remodeling result, although the title names it.
MOTS-c raised phosphorylated AMPK and lowered angiotensin II type 1 (AT-1) and endothelin B (ET-B) receptor expression.
In plain English: MOTS-c treatment significantly alleviated bone loss... MOTS-c increased phosphorylated AMPK levels, and compound C, an AMPK inhibitor, could partially abrogate the effects of the MOTS-c on osteoclastogenesis.
Ming W, Lu G, Xin S, Huanyu L, Yinghao J, Xiaoying L. · Biochem Biophys Res Commun (2016)
Mouse ovariectomy osteoporosis model, MOTS-c injected at 5 mg/kg a day for 12 weeks.
MOTS-c significantly reduced bone loss on micro-CT and inhibited RANKL-induced osteoclast differentiation.
MOTS-c raised phosphorylated AMPK, and the AMPK inhibitor compound C partially abrogated its effect on osteoclast formation in cells. The link to AMPK was not tested for the bone loss in the mice.
In plain English: Circulating MOTS-c reduced with age, but older (70-81 y) and middle-aged (45-55 y) men had ~1.5-fold higher skeletal muscle MOTS-c expression than young (18-30 y).
D'Souza RF, Woodhead JST, Hedges CP, Zeng N, Wan J, Kumagai H. · Aging (Albany NY) (2020)
Human observational study of plasma and skeletal-muscle MOTS-c across young, middle-aged and older healthy men
Circulating MOTS-c declined with age, while muscle MOTS-c expression was higher in older/middle-aged men and tracked slow-type myofiber markers
In older men, muscle MOTS-c was associated with better muscle quality (leg-press load relative to thigh cross-sectional area)
In plain English: MOTS-c has been used less frequently in disease treatment, and no effective method of applying MOTS-c in the clinic has been developed.
Zheng Y, Wei Z, Wang T. · Front Endocrinol (Lausanne) (2023)
Review of MOTS-c biology and its proposed roles in aging, cardiovascular disease, insulin resistance and inflammation
Describes nuclear translocation under metabolic stress, improved skeletal-muscle glucose metabolism, and an age-related decline in plasma levels
Explicitly states no effective clinical application of MOTS-c has been developed — underscoring the lack of human therapeutic evidence
In plain English: Among MDPs, mitochondrial ORF of the 12S rRNA type-c (MOTS-c) is the most associated with exercise... Systemic MOTS-c administration increases exercise performance by boosting skeletal muscle stress responses.
Yoon TK, Lee CH, Kwon O, Kim MS. · Diabetes Metab J (2022)
Review of MOTS-c within exercise-related mitohormesis (the beneficial response to low-level mitochondrial stress)
Summarizes that MOTS-c rises in skeletal muscle, circulation and hypothalamus with exercise, and that exogenous MOTS-c boosts performance and adipose thermogenesis in animal studies
Frames MOTS-c as a mediator of some salutary metabolic effects of exercise
In plain English: Increased β-amyloid or low MOTS-c are additive predictors to high on-clopidogrel platelet reactivity for adverse outcome in diabetics with CAD during 2-years follow-up.
Ikonomidis I, Katogiannis K, Kyriakou E, Taichert M, Katsimaglis G, Tsoumani M. · J Thromb Thrombolysis (2020)
121 type 2 diabetics on clopidogrel and aspirin after coronary revascularization, followed for 2 years, with results confirmed in a 90-patient external validation cohort. MOTS-c was measured in blood, not given.
MOTS-c below 167 ng/ml predicted cardiac death or acute coronary syndrome over 2 years (relative risk 3.8) after adjustment, and added to the risk from high on-clopidogrel platelet reactivity.
An association of the body's own MOTS-c with outcomes. It does not test giving MOTS-c.
In plain English: This is the first study to show increased lipid enhanced circulating MOTS-c whilst insulin attenuated the MOTS-c response in human... eight weeks of moderate exercise training did not show any changes in circulating MOTS-c levels.
Ramanjaneya M, Jerobin J, Bettahi I, Bensila M, Aye M, Siveen KS. · Clin Endocrinol (Oxf) (2019)
A human physiology study in women with PCOS and healthy controls: 5-hour intralipid or saline infusion with an insulin clamp in the last 2 hours, repeated after an 8-week exercise programme. Plasma MOTS-c measured by ELISA. No one was given MOTS-c.
Intralipid raised plasma MOTS-c to 232% of basal in controls and 349% in PCOS. Insulin blunted the rise significantly in PCOS (to 183%), while in controls the fall (to 165%) was not significant.
Eight weeks of moderate exercise training did not change circulating MOTS-c in either group.
In plain English: We suggest that the m.1382A>C polymorphism located in the MOTS-c encoding mtDNA, which is specific for the Northeast Asian population, may be among the putative biological mechanisms explaining the high longevity of Japanese people.
Fuku N, Pareja-Galeano H, Zempo H, Alis R, Arai Y, Lucia A. · Aging Cell (2015)
A short perspective piece with no new data, on mitochondrial-derived peptides including humanin and MOTS-c.
The authors suggest the m.1382A>C polymorphism in the MOTS-c coding region, specific to Northeast Asian populations, may help explain the high longevity of Japanese people, and say more research is needed.
A hypothesis. It does not test MOTS-c levels or treatment.