A peptide from an unexpected place
Mitochondria are the organelles responsible for producing ATP, the cell's primary energy currency. They have their own genome - a small circular DNA molecule, a remnant of the bacterial ancestor that was incorporated into eukaryotic cells roughly 1.5 billion years ago. The mitochondrial genome encodes only 37 genes, all of them well characterised as components of the respiratory chain or mitochondrial ribosomes.
In 2015, Changhan David Lee and colleagues at the University of Southern California published a paper in Cell Metabolism identifying a short open reading frame within the 12S ribosomal RNA gene of mitochondrial DNA. This sequence, when translated, produces a 16-amino acid peptide they named MOTS-C (Mitochondrial Open reading frame of the twelve S rRNA-c). The finding was notable: it was an actively translated peptide from a region of mitochondrial DNA not previously known to encode proteins.
What MOTS-C does in cell studies
In the original 2015 paper, MOTS-C was found to activate the AMPK (AMP-activated protein kinase) pathway, a central regulator of cellular energy sensing. AMPK is activated when the ratio of AMP to ATP rises - in other words, when energy supplies are low. AMPK activation promotes glucose uptake in muscle cells, inhibits anabolic processes that consume energy, and stimulates mitochondrial biogenesis.
The researchers found that MOTS-C could translocate from the cytoplasm to the nucleus in response to metabolic stress, where it appeared to regulate gene expression related to energy homeostasis. This nucleus-translocation behaviour is unusual for a peptide of its size and origin.
In cellular experiments, MOTS-C treatment increased glucose uptake in muscle cells and improved insulin sensitivity markers. In mouse models, exogenous MOTS-C administration reduced diet-induced obesity and improved glucose tolerance.
Exercise and MOTS-C
A 2021 study published in Nature Aging (Kim et al.) examined MOTS-C levels in response to exercise. Plasma MOTS-C concentrations increased during acute exercise in human participants, and higher circulating MOTS-C was associated with better metabolic parameters in older adults. The finding suggested that MOTS-C may be one of the mechanisms by which exercise produces systemic metabolic benefits - a "mitokine" released from active mitochondria in exercising muscle.
This concept of mitochondria as signalling organelles - releasing peptides that communicate metabolic state to distant tissues - has broader implications for understanding how exercise affects the whole body.
What remains to be understood
MOTS-C research is early-stage. The 2015 discovery paper, the subsequent exercise studies, and a growing number of in vitro and rodent studies are promising, but the peptide has not been studied in controlled human trials as an intervention. Mechanisms identified in cell culture and mouse models do not always translate directly to human physiology.
Key open questions include: the precise receptor(s) or binding partners through which MOTS-C acts (AMPK activation is a downstream effect; what is upstream?), the relationship between endogenous MOTS-C levels and disease states, and whether exogenous MOTS-C produces effects comparable to those seen in rodent studies in humans.
References: Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015. Kim SJ et al. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and biological aging. Nature Aging. 2021.
A peptide from an unexpected place
Mitochondria are the organelles responsible for producing ATP, the cell's primary energy currency. They have their own genome - a small circular DNA molecule, a remnant of the bacterial ancestor that was incorporated into eukaryotic cells roughly 1.5 billion years ago. The mitochondrial genome encodes only 37 genes, all of them well characterised as components of the respiratory chain or mitochondrial ribosomes.
In 2015, Changhan David Lee and colleagues at the University of Southern California published a paper in Cell Metabolism identifying a short open reading frame within the 12S ribosomal RNA gene of mitochondrial DNA. This sequence, when translated, produces a 16-amino acid peptide they named MOTS-C (Mitochondrial Open reading frame of the twelve S rRNA-c). The finding was notable: it was an actively translated peptide from a region of mitochondrial DNA not previously known to encode proteins.
What MOTS-C does in cell studies
In the original 2015 paper, MOTS-C was found to activate the AMPK (AMP-activated protein kinase) pathway, a central regulator of cellular energy sensing. AMPK is activated when the ratio of AMP to ATP rises - in other words, when energy supplies are low. AMPK activation promotes glucose uptake in muscle cells, inhibits anabolic processes that consume energy, and stimulates mitochondrial biogenesis.
The researchers found that MOTS-C could translocate from the cytoplasm to the nucleus in response to metabolic stress, where it appeared to regulate gene expression related to energy homeostasis. This nucleus-translocation behaviour is unusual for a peptide of its size and origin.
In cellular experiments, MOTS-C treatment increased glucose uptake in muscle cells and improved insulin sensitivity markers. In mouse models, exogenous MOTS-C administration reduced diet-induced obesity and improved glucose tolerance.
Exercise and MOTS-C
A 2021 study published in Nature Aging (Kim et al.) examined MOTS-C levels in response to exercise. Plasma MOTS-C concentrations increased during acute exercise in human participants, and higher circulating MOTS-C was associated with better metabolic parameters in older adults. The finding suggested that MOTS-C may be one of the mechanisms by which exercise produces systemic metabolic benefits - a "mitokine" released from active mitochondria in exercising muscle.
This concept of mitochondria as signalling organelles - releasing peptides that communicate metabolic state to distant tissues - has broader implications for understanding how exercise affects the whole body.
What remains to be understood
MOTS-C research is early-stage. The 2015 discovery paper, the subsequent exercise studies, and a growing number of in vitro and rodent studies are promising, but the peptide has not been studied in controlled human trials as an intervention. Mechanisms identified in cell culture and mouse models do not always translate directly to human physiology.
Key open questions include: the precise receptor(s) or binding partners through which MOTS-C acts (AMPK activation is a downstream effect; what is upstream?), the relationship between endogenous MOTS-C levels and disease states, and whether exogenous MOTS-C produces effects comparable to those seen in rodent studies in humans.
References: Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015. Kim SJ et al. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and biological aging. Nature Aging. 2021.
