MOTS-c

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is, like humanin, a signalling peptide encoded in the mitochondria's own genome. It was described in 2015 as a short reading frame inside the mitochondrial 12S rRNA gene [1]. It is present in plasma, and a review reports that levels fall with age [4].

Mouse evidence. In mice, MOTS-c injections prevented age-related and high-fat-diet insulin resistance and diet-induced obesity [1]. In obese mice it also lowered plasma metabolites linked to obesity and diabetes, and increased fat burning [5]. Daily injections improved running performance in young, middle-aged and old mice. Treatment three times a week, started in very old mice, improved grip strength, gait and walking [2].

Human evidence. No study has given MOTS-c to people. The human data are about the body's own peptide:

• In 10 young men, a hard cycling session raised MOTS-c 11.9-fold in thigh muscle and about 1.5-fold in blood. Blood levels returned to baseline within 4 hours [2].
• Plasma MOTS-c was similar in lean and obese adults. It tracked insulin resistance only in the lean group [6].
• A fat infusion raised plasma MOTS-c, insulin damped the rise, and 8 weeks of moderate exercise training did not change resting levels [7].
• An Asian-specific mitochondrial DNA variant (m.1382A>C) changes one amino acid (K14Q). It was linked to type 2 diabetes in men, and the variant peptide did not work in mice [8].

One caution applies to all the human blood data. When anti-doping chemists built a mass-spectrometry test, they could not confirm the levels a commercial ELISA kit had reported (45.9–218.5 ng/mL) [3]. Another study reported plasma levels below 1 ng/mL [6].

MOTS-c acts mainly on skeletal muscle. It inhibits the folate cycle and the de novo purine synthesis linked to it, and this activates AMPK, the cell's energy-shortage sensor [1]. Under metabolic stress such as glucose restriction, it moves into the nucleus in an AMPK-dependent way. There it regulates a broad set of genes, including antioxidant-response genes, and interacts with the transcription factor NRF2 [9]. The authors present this as evidence that mitochondrial DNA can directly regulate nuclear genes.

In mice it also changed skeletal-muscle metabolism and gene expression, and helped muscle cells adapt to metabolic stress [2]. Male mice responded to it but female mice did not [8].

There are no human safety data. A 2026 review of peptides sold directly to patients lists MOTS-c among unapproved compounds whose animal results look favourable but whose human safety data are scarce [12]. Anti-doping labs have developed a test for synthetic MOTS-c in plasma [3].