MOTS-c

This is the discovery paper for MOTS-c. The authors identified a short open reading frame within the mitochondrial 12S rRNA that encodes a 16-amino-acid peptide, which they named MOTS-c. In skeletal muscle cell culture, MOTS-c was associated with increased glucose uptake and activation of AMP-activated protein kinase (AMPK). The proposed upstream mechanism was inhibition of the folate cycle, leading to accumulation of the AICAR intermediate — a known direct AMPK agonist. In mouse models, MOTS-c administration was associated with attenuation of high-fat-diet-induced obesity, improved insulin sensitivity on glucose and insulin tolerance testing, and reduced age-dependent insulin resistance. Endogenous circulating MOTS-c was detected in mouse and human plasma, supporting the authors' framing of MOTS-c as a mitochondrially-encoded signaling peptide.

Scientists discovered a tiny protein hidden inside a piece of mitochondrial DNA that no one had previously recognized as a gene. They named it MOTS-c. When they tested it in muscle cells, the cells took in more glucose and activated a master energy-sensing switch called AMPK — the same switch that exercise and the diabetes drug metformin flip on. When they gave MOTS-c to mice on a high-fat diet, the mice gained less weight and handled blood sugar better than untreated mice. Older mice also became more responsive to insulin. The discovery was significant because it showed that mitochondria — long thought of as just cellular power plants — also send chemical messages to the rest of the cell.

This follow-up study examined the subcellular trafficking of MOTS-c. Under basal conditions, MOTS-c was detected primarily in the cytoplasm and mitochondria. Under metabolic stress — including glucose restriction and oxidative stress — MOTS-c was reported to translocate to the nucleus. Nuclear MOTS-c was associated with regulation of stress-adaptive nuclear gene expression, including genes involved in antioxidant response and metabolic homeostasis. The authors describe MOTS-c as the first identified mitochondrial-encoded peptide shown to act directly in the nucleus, establishing a direct mitochondrial-to-nuclear signaling axis distinct from classical retrograde signaling.

Researchers tracked where MOTS-c goes inside a cell. Under normal conditions it sits mostly in the cell body and within the mitochondria. But when the cell is stressed — for example, when sugar runs low or oxygen-related damage builds up — MOTS-c moves into the cell's nucleus, the compartment that contains the main genome. Once there, it helps switch on genes that the cell uses to handle that stress. This was the first time a peptide encoded by mitochondrial DNA had been observed acting directly on nuclear genes, suggesting a previously unknown communication channel between the two genomes a cell carries.