MOTS-c: Mitochondrial-Derived Peptide Signalling to the Nucleus

Origin and the class it defines

Lee et al. (Cell Metab, 2015) reported MOTS-c as a mitochondrial-derived peptide promoting metabolic homeostasis and reducing obesity and insulin resistance in mice. The finding of note was not the metabolic effect alone but that the mitochondrial genome encodes a peptide with signalling function outside the organelle.

The same group's 2016 review in Free Radical Biology and Medicine sets out the regulation of muscle and fat metabolism. Mohtashami et al. (Int J Mol Sci, 2022) and Zheng et al. (Front Endocrinol, 2023) provide more recent overviews.

Proposed mechanisms

The originally proposed mechanism involves the folate cycle and de novo purine biosynthesis, with accumulation of AICAR leading to AMPK activation. AMPK activation is a plausible and well-understood route to the reported metabolic effects.

Kim et al. (Cell Metab, 2018) reported that MOTS-c translocates to the nucleus under metabolic stress and regulates nuclear gene expression. This is the mechanistically most significant result in the literature: retrograde signalling from the mitochondrial genome to the nuclear one, with the peptide as the messenger.

Several recent papers implicate additional pathways. Lu et al. (Eur J Pharmacol, 2023) report suppression of ferroptosis via PPAR-gamma signalling. Zhang et al. (Antioxidants, 2024) report an Nrf2-dependent mechanism in radiation pneumonitis. Whether these represent distinct mechanisms or downstream consequences of AMPK activation is not resolved.

Breadth and independence of the recent literature

Recent primary work spans several systems and groups: Yin et al. (Pharmacol Res, 2022) on gestational diabetes, Lu et al. (Int J Mol Sci, 2019) on adipose thermogenic activation in cold adaptation, Yin et al. (Adv Sci, 2024) on ovarian cancer progression via USP7-mediated LARS1 deubiquitination, Pham et al. (Front Physiol, 2025) on mitochondrial respiration in the type 2 diabetic heart, and Shi et al. (Autophagy, 2026) on lysosomal membrane permeability in soft tissue transplantation.

This breadth across independent groups is what distinguishes MOTS-c from most compounds in this catalogue. It is the difference between a literature and a body of work from one laboratory.