How Does MOTS-c Work?

A peptide encoded in mitochondrial DNA

Mitochondria carry their own small genome. After an earlier mitochondrial short open reading frame was found to encode the signaling peptide humanin, a 2015 study searched for others and reported one inside the mitochondrial 12S rRNA gene. It encodes a 16-amino-acid peptide the authors named MOTS-c, short for mitochondrial open reading frame of the 12S rRNA-c.Animal study · PMID 25738459

The same paper described MOTS-c as regulating insulin sensitivity and metabolic homeostasis, with skeletal muscle as its apparent primary target organ. The authors presented it as evidence that mitochondria may regulate metabolism at the cellular and whole-organism level through peptides encoded within their own genome.Animal study · PMID 25738459

The folate pathway and AMPK

The 2015 study proposed a specific chain of events inside cells. MOTS-c inhibits the folate pathway and the de novo purine biosynthesis tethered to it, and this leads to activation of AMPK, the AMP-activated protein kinase that senses cellular energy status. That sequence is the most cited answer to how MOTS-c works.Animal study · PMID 25738459

In the same study, MOTS-c in mice prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity. These are mouse findings; the paper did not test the pathway in people.Animal study · PMID 25738459

Later work kept AMPK at the centre. In a 2026 study of cultured myotubes, MOTS-c raised AMPK phosphorylation by 103.1% and PGC-1α mRNA by 84.6%. In an 8-week study of diabetic sand rats, exercise intensity (p = 0.022) and diabetes (p = 0.008) both significantly influenced AMPK protein levels, alongside MOTS-c protein measured by ELISA.Animal study · PMID 42266945Animal study · PMID 38636847

Moving into the nucleus under stress

A 2018 study added a second mechanism. It showed that MOTS-c translocates to the nucleus and regulates nuclear gene expression after metabolic stress, and that this depends on AMPK. Until then, the nuclear genome was not known to be actively controlled by factors encoded in mitochondrial DNA.In vitro · PMID 29983246

Under glucose restriction, nuclear MOTS-c regulated a broad range of genes, including those with antioxidant response elements, and interacted with stress-responsive transcription factors that regulate those elements, such as NRF2 (NFE2L2). The authors concluded that the mitochondrial and nuclear genomes co-evolved to encode factors that cross-regulate each other.In vitro · PMID 29983246

The two mechanisms connect. AMPK activation is the downstream result of the folate-pathway effect described in 2015, and AMPK is also what the 2018 study found to be required for nuclear entry. In that account, MOTS-c both feeds into the cell's energy sensor and depends on it to reach the nucleus, where its targets include antioxidant response genes.Animal study · PMID 25738459In vitro · PMID 29983246

Exercise and MOTS-c levels

A 2021 study connected MOTS-c to physical activity. In people, exercise induced endogenous MOTS-c expression in skeletal muscle and in circulation. In mice, MOTS-c was associated with higher physical performance at young (2 months), middle (12 months) and old (22 months) ages, and it regulated nuclear genes related to metabolism and proteostasis, skeletal muscle metabolism, and myoblast adaptation to metabolic stress.Animal study · PMID 33473109

The same study reported that intermittent MOTS-c started late in life, at 23.5 months, was associated with greater physical capacity and healthspan in mice. Its authors concluded that aging is regulated by genes in both the mitochondrial and nuclear genomes.Animal study · PMID 33473109

A 2025 study compared marathon runners with sedentary people and found a close association between serum MOTS-c and aerobic exercise capacity. In mice, long-term endurance training was linked with higher skeletal muscle mitochondrial respiration, which the authors attributed to MOTS-c secretion and activation of the AMPK/PGC-1α pathway.Animal study · PMID 39706498

The direction of cause in the human data is not established. The runner study measured serum MOTS-c and aerobic capacity at one point in time, and the 2021 study measured endogenous MOTS-c after exercise. Both show that MOTS-c levels move with physical activity in people; neither tested what supplying the peptide does in people.Animal study · PMID 39706498Animal study · PMID 33473109

Disease models in rodents

In a 2026 mouse model of cancer cachexia using Colon-26 tumors, the mice lost about 9% of body weight. MOTS-c did not stop total body weight or fat loss, but quadriceps weight was 12% higher than in tumor-bearing controls (p < 0.05). The cachexia-related rise in Atrogin-1 (8.6-fold) and MuRF1 (16-fold) was attenuated, and PGC-1α protein was 143% higher.Animal study · PMID 42266945

In a 2023 rat model of type 2 diabetes, MOTS-c alone or combined with exercise for 8 weeks was associated with less myocardial ultrastructural damage and with higher SOD, catalase, Keap1, Nrf2 and phosphorylated AMPK. Combining MOTS-c with exercise lowered myocardial MDA, a lipid peroxidation marker, more than either alone.Animal study · PMID 37957221

In the 2024 sand rat study, the moderate-intensity exercise group with diabetes showed higher PGC-1α, MOTS-c and GLUT4 protein and insulin resistance below that of the other diabetic groups (p < 0.001). This study measured endogenous MOTS-c as a response to exercise; it did not supply the peptide.Animal study · PMID 38636847

The cachexia study combined cultured myotubes, which supplied the AMPK and PGC-1α measurements, with tumor-bearing mice. In the mice, the authors linked the muscle findings to FOXO signaling: alongside the attenuated atrogene rise, inhibitory phosphorylation of FOXO1 was 80% higher and phosphorylation of FOXO3a 39% lower. They concluded that MOTS-c partly offsets muscle loss in this model through FOXO-driven catabolic signaling and mitochondrial biogenesis.Animal study · PMID 42266945

What the MOTS-c evidence does not settle

The mechanistic chain of folate pathway inhibition, purine synthesis, AMPK activation and nuclear translocation was established in cells and mice. The human data cited here are observational: exercise-induced changes in endogenous MOTS-c and a comparison of serum levels between runners and sedentary people.Animal study · PMID 25738459In vitro · PMID 29983246Animal study · PMID 33473109Animal study · PMID 39706498

The cachexia study noted that studies of MOTS-c in people with cancer cachexia are still needed. Two of the foundational papers also disclose that some authors were consultants for, and shareholders of, a company named in their conflict statements, which is worth weighing alongside the independent studies from other groups.Animal study · PMID 42266945In vitro · PMID 29983246Animal study · PMID 33473109

The studies at a glance

Key MOTS-c studies by model. Results are as reported in each paper's abstract.

Frequently asked questions