MOTS-c

The overview

What is MOTS-c?

In cell-culture systems, MOTS-c acts as a regulatory microprotein that modulates the cytosolic folate–methionine one-carbon cycle. By attenuating de novo purine biosynthesis, it promotes accumulation of the intermediate AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), an allosteric activator of AMP-activated protein kinase (AMPK). This represents a non-canonical route to AMPK signaling that is largely independent of acute changes in the cellular AMP:ATP ratio. Under metabolic-stress conditions (e.g., glucose restriction or oxidative challenge) in vitro, MOTS-c translocates from the cytosol to the nucleus in an AMPK-dependent manner, where it associates with stress-responsive transcription factors including NFE2L2/NRF2 and occupies antioxidant-response-element (ARE) and other regulatory regions, shaping nuclear gene-expression programs related to metabolism and redox balance. Reported receptor/signaling readouts in model systems include AMPK phosphorylation, modulation of insulin-stimulated glucose uptake pathways, and altered mitonuclear transcriptional crosstalk. These are mechanistic, model-system observations of signaling behavior and are not statements of clinical efficacy.

In the research

Where MOTS-c shows up

The areas researchers focus on with MOTS-c - and why it has the science community paying attention.

• AMPK signaling activation in cultured cells and rodent tissue models
• Mitonuclear retrograde communication and stress-induced nuclear translocation
• Folate/one-carbon metabolism and de novo purine biosynthesis modulation (AICAR accumulation)
• NRF2/ARE-mediated antioxidant transcriptional response in vitro
• Mitochondrial-derived peptide (MDP) biology and microprotein discovery
• Skeletal-muscle metabolic gene-expression and exercise-responsive signaling in animal models

By the numbers

The facts that matter

To the molecule

Molecular specifications

Sourced, not claimed

The science behind it

The peer-reviewed studies behind MOTS-c, linked so you can read them yourself.

1. Lee, C., et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and prevents obesity and insulin resistance. Cell Metabolism.
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2. Reynolds, J. C., et al. (2021). MOTS-c promotes physical performance and prevents age-associated metabolic decline. Nature Communications.
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Straight answers

Questions, answered