Research

MOTS-c and mitochondria: a peptide encoded in mitochondrial DNA

How a peptide encoded in the mitochondrial 12S rRNA gene became a model for mitochondrial-to-nuclear signalling, and what remains uncertain about its origin.

By the MOTS-C Peptide editorial teamLast reviewed November 11, 2026Sources: editorially approved

Short answer

MOTS-c is encoded inside the mitochondrial genome, within the 12S ribosomal RNA gene MT-RNR1 [Lee et al. 2015] [UniProt 2026]. That origin is what makes it scientifically interesting: it belongs to a small set of peptides encoded by mitochondria rather than by the nucleus, and it has been reported to act outside the organelle. 133 indexed records relate to mitochondrial biology.

Schematic, not to scale. It shows where MOTS-c has been reported, not how it acts. Nuclear entry comes from cell experiments under metabolic stress; it has not been demonstrated in human tissue. See the studies behind each step.

A second genome in every cell

Mitochondria carry their own circular DNA, a remnant of the bacterial ancestry of the organelle. For decades it was understood to encode 13 respiratory-chain proteins plus the transfer and ribosomal RNAs needed to translate them. The discovery of peptides encoded within those RNA genes extended that list in an unexpected direction.

Humanin came first, described in 2001 from a search for factors protecting neurons [Hashimoto 2001]. MOTS-c followed in 2015, from a 51-base open reading frame inside the 12S rRNA gene [Lee et al. 2015]. A family of small humanin-like peptides encoded in the 16S rRNA region was subsequently described [Cobb 2016]. Collectively these are called mitochondrial-derived peptides.

Signalling in the less-studied direction

Most known communication between the two genomes runs from nucleus to mitochondrion: nuclear genes encode most mitochondrial proteins. MOTS-c attracted attention because the reported traffic runs the other way. Under metabolic stress in cultured cells, the peptide translocated to the nucleus in an AMPK-dependent manner and was linked to stress-response gene expression [Kim et al. 2018].

If that holds in living tissue, it is a genuinely different kind of signal: a peptide product of the mitochondrial genome acting on nuclear transcription. The conditional matters. The work was done in cultured cells under imposed stress, and a human muscle study found muscle MOTS-c expression was not associated with antioxidant-response-element gene expression. See mechanism of action.

Related peptides and shared context

Studies frequently measure MOTS-c alongside humanin, and senescence work has reported both elevated in senescent fibroblasts [Kim et al. 2018]. Records where another mitochondrial-derived peptide is the main subject are tagged in the index so they can be filtered out: see records about related peptides.

Indexed mitochondrial records

Human observational: 31
Animal study (in vivo): 41
Tissue / sample study (ex vivo): 4
Cell study (in vitro): 10
Analytical / methods: 3
Review: 44

133 indexed records. Open this set in the evidence explorer.

Indexed MOTS-c mitochondrial-biology studies ranked by evidence tier
Study	Model	What was reported	Limitations	Tier
Zhang 2026 Antioxidants (Basel) Endogenous MOTS-c measured	Human obs. Healthy young males stratified as elite track and field athletes, recreationally active and sedentary; serum MOTS-c and fitness testing	Measured progressively higher serum MOTS-c from sedentary to recreationally active to elite athlete groups of young males. Reported strong positive correlations of serum MOTS-c with peak oxygen uptake, superoxide dismutase, back muscle endurance and post-fatigue force, a strong inverse correlation with post-exercise malondialdehyde, and no significant correlation with handgrip strength.	Very small groups of 10 young males each; cross-sectional design precludes causal inference; multiple strong correlations in a small sample risk overfitting.	Evidence tier B
Suliman 2026 Antioxidants (Basel) Related mitochondrial peptide	Human obs. Adults with kidney failure undergoing living-donor kidney transplantation and controls; serum AGEs, RAGE isoforms and MDPs by ELISA	Measured higher advanced glycation end-products and lower mitochondrial-derived peptides, including MOTS-c, in adults with chronic kidney disease compared with controls. Reported that MOTS-c was inversely associated with advanced glycation end-products and with the AGEs/sRAGE ratio, while humanin was independently associated with AGEs and sRAGE measures.	Cross-sectional design with MOTS-c one of several peptides measured; single-centre transplantation cohort; ELISA-based peptide quantification without orthogonal confirmation.	Evidence tier B
Horwath 2026 Exp Physiol Endogenous MOTS-c measured	Human obs. Adults with cerebral palsy using running frames and typically developing adults and adolescents; plasma MDPs before and after endurance exercise	Measured plasma MOTS-c, humanin and SHMOOSE in adults with cerebral palsy and typically developing participants and found comparable basal levels despite lower muscle mass and peak oxygen uptake in the cerebral palsy group. Reported no or only modest changes in circulating MDPs after an acute endurance exercise bout, with no differences between groups.	Small group sizes not reported in the abstract; single post-exercise sampling point; in-house ELISA without external validation and heterogeneous exercise modes between groups.	Evidence tier B
Sonay 2026 J Clin Med Endogenous MOTS-c measured	Human obs. Patients with Hashimoto's thyroiditis and age- and sex-matched healthy controls; circulating MOTS-c	Measured lower circulating MOTS-c in patients with Hashimoto's thyroiditis than in matched controls, with inverse correlations with body mass index, fasting glucose, HbA1c, HOMA-IR, thyroid-stimulating hormone, C-reactive protein and thyroid autoantibodies. Reported that Hashimoto's thyroiditis and HOMA-IR were independent determinants of lower MOTS-c in regression analysis.	Cross-sectional design cannot establish direction; single-centre sample measured by ELISA at one time point; medication and iodine status largely unaccounted for beyond levothyroxine use.	Evidence tier B
Musolino 2026 Int Urol Nephrol Endogenous MOTS-c measured	Human obs. Stable peritoneal dialysis patients; MOTS-c measured in serum, urine and peritoneal dialysate	Measured MOTS-c in serum, urine and dialysate of peritoneal dialysis patients and reported that higher urinary MOTS-c was associated with lower advanced oxidation protein products and with higher pulse wave velocity and left ventricular systolic function. Reported that higher dialysate MOTS-c was associated with lower pulse wave velocity and lower blood pressure.	Small single-centre pilot with no control group and cross-sectional correlations only; multiple comparisons across three compartments without adjustment.	Evidence tier B
Peng 2026 Biomedicines Endogenous MOTS-c measured	Human obs. Patients with acute myocardial infarction undergoing percutaneous coronary intervention; peripheral and intracoronary serum MOTS-c	Measured lower postoperative peripheral serum MOTS-c in patients with myocardial ischemia-reperfusion injury than in those without, while preoperative peripheral and intracoronary levels did not differ. Reported that postoperative peripheral MOTS-c was an independent factor in multivariable regression, with an area under the curve of 0.648 for discriminating injury.	Small single-centre cross-sectional sample; modest discrimination; no longitudinal or repeated sampling, and residual confounding by procedural factors is likely.	Evidence tier B
Kutuk 2026 Sci Rep Endogenous MOTS-c measured	Human obs. Women with polycystic ovary syndrome and age- and BMI-matched controls; serum ELISA and vastus lateralis biopsies	Measured lower circulating MOTS-c concentrations and lower skeletal muscle MOTS-c expression in women with polycystic ovary syndrome than in matched controls. Reported that serum MOTS-c was inversely associated with total testosterone and total cholesterol in this cohort.	Cross-sectional case-control design cannot establish direction; muscle expression was assessed only in a subgroup; single-centre sample of women with weak correlation coefficients.	Evidence tier B
Yoon 2026 J Clin Transl Endocrinol Endogenous MOTS-c measured	Human obs. Lean adult controls and adults with obesity scheduled for bariatric surgery; adipose tissue from lean kidney donors and participants with obesity	Found higher circulating MOTS-c in adults with obesity than in lean adults, with BMI and HOMA-IR each independently predicting higher levels and a nonlinear relationship with HOMA-IR. Reported that adipose tissue MOTS-c expression did not differ between groups and did not correlate with circulating MOTS-c. Measured no change in circulating MOTS-c 6 months after bariatric surgery despite lower BMI in the 10 participants followed.	Small exploratory sample with only 10 participants followed after surgery, cross-sectional group comparison, adipose tissue controls drawn from kidney donors rather than the lean comparison group, and no sex-stratified analysis reported.	Evidence tier B
Erol 2025 Cureus Endogenous MOTS-c measured	Human obs. Patients newly diagnosed with multiple myeloma sampled before and after frontline treatment	Measured serum MOTS-c before and after frontline treatment in adults with newly diagnosed multiple myeloma and reported a substantial post-treatment increase in responders, with little or no change in refractory cases. Found that post-treatment MOTS-c values correlated inversely with changes in calcium and neutrophil count. Reported limited standalone predictive capacity for MOTS-c in this cohort.	Small single-cohort sample of 29 patients with no untreated comparison group, heterogeneous frontline regimens, and exploratory correlational analyses without adjustment or external validation.	Evidence tier B
Cao 2025 J Am Heart Assoc Several	Human obs. Patients with unstable angina or acute myocardial infarction and normal controls; cultured cells under hypoxia	Reported higher serum MOTS-c and thiobarbituric acid reactive substances in patients with acute coronary syndrome than in controls, with a positive correlation between the two. Found that the ratio of MOTS-c to thiobarbituric acid reactive substances discriminated patients who went on to have major adverse cardiac events over 18 months of follow-up in the acute myocardial infarction group. Reported in cultured cells that oxidative stress raised MOTS-c levels and that MOTS-c exposure lowered hypoxia-induced oxidative stress.	Single-timepoint admission sampling in one recruited cohort with no external validation of the reported cut-off values, modest discrimination statistics, and in vitro work in an unspecified cell system reported only in summary.	Evidence tier B

For the molecule itself, see molecular data; for how the peptide has been studied in people, see human studies.

Frequently asked questions

What is a mitochondrial-derived peptide?

A peptide encoded within the mitochondrial genome rather than the nuclear genome. Humanin, described in 2001, was the first; MOTS-c followed in 2015, and a family of small humanin-like peptides has since been described in the 16S rRNA region.

Where is MOTS-c encoded?

Within MT-RNR1, the mitochondrial gene for 12S ribosomal RNA. A short open reading frame inside that gene encodes the 16-amino-acid peptide.

What is mitochondrial-to-nuclear signalling?

Communication running from the mitochondrion to the nucleus, rather than the better-studied direction. MOTS-c is cited as an example because cell studies reported it entering the nucleus under metabolic stress and associating with stress-response genes.

Is MOTS-c a mitokine?

The term is used for mitochondrial signals acting beyond the organelle, and MOTS-c is often described that way. Since no receptor has been identified, the label describes a proposed role rather than a demonstrated signalling mechanism.

References

Lee C, Zeng J, Drew BG et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. PubMed 25738459 · doi:10.1016/j.cmet.2015.02.009 · Study record[Animal, tier C]
Kim KH, Son JM, Benayoun BA et al. (2018). The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metab. PubMed 29983246 · doi:10.1016/j.cmet.2018.06.008 · Study record[Cells, tier D]
Kim SJ, Mehta HH, Wan J et al. (2018). Mitochondrial peptides modulate mitochondrial function during cellular senescence. Aging (Albany NY). PubMed 29886458 · doi:10.18632/aging.101463 · Study record[Cells, tier D]
UniProt Consortium (2026-09-02). UniProtKB A0A0C5B5G6 (MOTSC_HUMAN): Mitochondrial-derived peptide MOTS-c. Source[retrieved 2026-11-11]
Hashimoto Y et al., Proc Natl Acad Sci U S A (2001-05-22). A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Source[retrieved 2026-11-11]
Cobb LJ et al., Aging (Albany NY) (2016-04). Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Source[retrieved 2026-11-11]
U.S. Food and Drug Administration (2026-05-11). FDA Briefing Document: MOTS-c-Related Bulk Drug Substances (MOTS-c (free base) and MOTS-c acetate). Source[retrieved 2026-11-11]