MOTS-c, the Exercise Signal Written Into Your Mitochondrial DNA

This clinic takes its name from the mitochondrion, the structure inside your cells that turns food and oxygen into usable energy, so I pay attention when patients ask about MOTS-c, a small peptide that mitochondria make from their own DNA. If exercise raises MOTS-c, and MOTS-c improves physical performance in old mice, can an injection deliver some of what exercise does? The biology behind that question is some of the most interesting I've read in the past decade, and the human evidence for the injection is almost nonexistent.

A hormone encoded in mitochondrial DNA

Mitochondria do more than make energy, because they also send hormone-like signals to the rest of the body. They descend from bacteria that took up residence inside our ancestors' cells, and they still carry their own small loop of DNA, separate from the chromosomes in the nucleus and passed down from your mother. In 2015, Changhan Lee, Pinchas Cohen and colleagues at the University of Southern California reported in Cell Metabolism that a short open reading frame, a stretch of genetic code too small to have been counted as a gene, sits inside the mitochondrial 12S ribosomal RNA gene. It encodes a peptide, a short chain of amino acids, only 16 units long [1]. They named it MOTS-c, and it joined humanin, an earlier discovery, among the mitochondrial-derived peptides.

MOTS-c acts mainly on skeletal muscle, where it inhibits the folate cycle and the purine synthesis tied to it, which activates AMP-activated protein kinase (AMPK), the enzyme that senses when a cell is running low on fuel and shifts it toward burning glucose and fat [1]. Mice treated with MOTS-c were protected from the insulin resistance that normally arrives with age and with a high-fat diet, and they didn't develop diet-induced obesity [1]. I've argued before that struggling mitochondria sit near the root of insulin resistance, and that insulin resistance fails differently in muscle, liver and fat, so a mitochondrial signal aimed at muscle fits that picture well.

The mitochondrial genome regulates the nuclear one

Under metabolic stress, MOTS-c leaves the mitochondria and enters the nucleus. Biologists have long known that nuclear genes govern the mitochondrial genome, but no one had shown a factor encoded in mitochondrial DNA doing the reverse. Kim and colleagues, in a 2018 cell study in Cell Metabolism, deprived cells of glucose and watched MOTS-c move into the nucleus in an AMPK-dependent manner, where it regulated a broad range of genes, including those with antioxidant response elements [2]. This means the two genomes, which have shared a cell since long before animals existed, evolved to regulate each other.

Exercise raises it, and treated mice performed better

Exercise is the best-documented way to raise your own MOTS-c. Reynolds and colleagues, in a 2021 paper in Nature Communications, reported that exercise induced MOTS-c in human skeletal muscle and in the circulation, and that MOTS-c treatment enhanced physical performance in young (2 months), middle-aged (12 months) and old (22 months) mice [3]. Intermittent treatment begun at 23.5 months, late life for a mouse, still improved physical capacity and healthspan [3].

The other human exercise studies are small and less tidy. When a Swedish trial randomized 30 volunteers to 45 minutes of cycling, a leg resistance session, or rest, endurance exercise significantly raised circulating humanin, while MOTS-c showed only a trend toward an increase, and resting levels didn't correlate with fitness [4]. In a secondary analysis of a randomized trial in 49 breast cancer survivors, 16 weeks of combined aerobic and resistance training raised plasma MOTS-c among the non-Hispanic White women but not among the Hispanic women [5].

A natural experiment in Japanese DNA

Human genetics offers the closest thing we have to a test of what MOTS-c does in people. A mitochondrial DNA variant called m.1382A>C, specific to Northeast Asian populations, replaces the lysine at position 14 of the peptide with a glutamine, producing a form known as K14Q. In 2015 Fuku and colleagues proposed that this variant might be among the biological explanations for the exceptional longevity of the Japanese, which was a hypothesis and not a tested finding [6]. In 2021 Zempo and colleagues pooled three cohorts totaling 27,527 people and found that men who carried the variant, but not women, had a higher prevalence of type 2 diabetes, and in one of those cohorts the excess appeared only among men in the lowest third of physical activity [7]. When the same group injected high-fat-fed male mice, normal MOTS-c reduced weight and improved glucose tolerance, and K14Q MOTS-c did neither [7].

My read is that carrying a weaker version of the peptide costs a man little while he stays active and costs him more once he becomes sedentary, which is the pattern I'd expect from an exercise signal. These are associations in cohorts and can't prove cause, though the mouse experiment points in the same direction.

Blood levels in people tell an inconsistent story

Studies that compare MOTS-c blood levels between healthy and sick people are observational, and they disagree with each other. A 2024 meta-analysis pooled seven studies with 602 participants and found lower MOTS-c in people with type 2 diabetes, yet higher MOTS-c in people with obesity [8]. Part of the problem is measurement, because when anti-doping scientists in Cologne built a mass spectrometry assay for MOTS-c in 2019, they couldn't confirm the concentrations that a commercial ELISA, an antibody-based test kit, had reported in 20 healthy volunteers [9]. Until laboratories agree on how much MOTS-c circulates in a healthy person, I don't think a blood level can guide treatment.

What no one has tested

No published randomized trial has given MOTS-c to humans. I searched PubMed for one and found exercise studies, cohort studies and animal experiments, and nothing that establishes a dose, how long an effect lasts, or what a year of injections does. A biotechnology company took a MOTS-c analog into early-phase human testing, but I can't find those results in any PubMed-indexed journal, so I have nothing to evaluate. A 2026 review in Sports Medicine of unapproved peptides marketed directly to patients, MOTS-c among them, concluded that many show favorable outcomes in animal models while rigorous human safety data are scarce and the potential for serious harm exists [10]. The compounded MOTS-c injection we prescribe isn't FDA-approved, and no FDA-approved form of the peptide exists.

The cautions I apply come from the mechanism and are my own reasoning, since no trial has produced safety findings. MOTS-c inhibits the folate cycle [1], and a developing fetus depends on folate, so I won't prescribe it during pregnancy, while breastfeeding, or to anyone trying to conceive. A peptide that improves insulin sensitivity in mice could plausibly add to the effect of insulin or a sulfonylurea, so anyone taking those drugs needs a plan for low blood sugar before starting. I'd also withhold it from children, adolescents and anyone with an active cancer until someone studies those groups. If you compete in a drug-tested sport, anti-doping laboratories already have a validated test for synthetic MOTS-c [9], so treat it as off limits and confirm with your anti-doping authority.

How we use it

Exercise comes first, because it raises MOTS-c in your own muscle [3] and carries decades of trial evidence for nearly every outcome patients hope a peptide will deliver.

• Train most days, combining endurance work, which produced the clearer peptide response in the Swedish trial [4], with the resistance training that protects muscle as you age.
• Protect the mitochondria you have. Sleep restores the cell's energy supply, and I've laid out the case that linoleic acid from industrial seed oils impairs mitochondrial membranes, so build your diet from single-ingredient whole foods.
• Track fasting insulin, glucose and body composition, so you can tell whether anything you add is working.

We consider MOTS-c for adults who already train, whose labs we follow, and who understand they're trying a peptide supported by mouse experiments and human genetics and not by a human trial. We prescribe it for a defined period alongside training, recheck those same markers, and stop it if nothing measurable changes.

Whether injecting MOTS-c reproduces the benefit of earning it through exercise remains untested in people, and until someone runs that trial I'll treat the injection as an experiment and the exercise as the therapy.

Ask a provider about MOTS-c

References

1. Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015. PMID: 25738459
2. Kim KH, Son JM, Benayoun BA, et al. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metab. 2018. PMID: 29983246
3. Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021. PMID: 33473109
4. von Walden F, Fernandez-Gonzalo R, Norrbom J, et al. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. J Appl Physiol (1985). 2021. PMID: 34351816
5. Dieli-Conwright CM, Sami N, Norris MK, et al. Effect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors. Sci Rep. 2021. PMID: 34413391
6. Fuku N, Pareja-Galeano H, Zempo H, et al. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell. 2015. PMID: 26289118
7. Zempo H, Kim SJ, Fuku N, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). 2021. PMID: 33468709
8. Zhou Q, Yin S, Lei X, et al. The correlation between mitochondrial derived peptide (MDP) and metabolic states: a systematic review and meta-analysis. Diabetol Metab Syndr. 2024. PMID: 39160573
9. Knoop A, Thomas A, Thevis M. Development of a mass spectrometry based detection method for the mitochondrion-derived peptide MOTS-c in plasma samples for doping control purposes. Rapid Commun Mass Spectrom. 2019. PMID: 30394592
10. Mendias CL, Awan TM. Safety and Efficacy of Approved and Unapproved Peptide Therapies for Musculoskeletal Injuries and Athletic Performance. Sports Med. 2026. PMID: 41966639