What Is MOTS-c?

MOTS-c belongs to a small family called mitochondrial-derived peptides. They are short proteins coded not in the nucleus but in the DNA of mitochondria. The first of them to be found was humanin; MOTS-c was the next major discovery.

A Gene Within a Gene

Mitochondrial DNA contains a gene for 12S ribosomal RNA, a component of the machinery that builds proteins inside mitochondria. Within that gene, researchers found a short open reading frame, a stretch of code that can be read as instructions for a peptide. It produces 16 amino acids: MRWQEMGYIFYPRKLR.

How It Works in Cells

• Folate cycle: MOTS-c slows the folate cycle and the linked production of purines, building blocks of DNA.
• AICAR build-up: this causes a natural compound called AICAR to accumulate in the cell.
• AMPK activation: AICAR switches on AMPK, an enzyme that acts as the cell's energy sensor and promotes the use of glucose and fat.
• Trip to the nucleus: under stress, such as a shortage of glucose, MOTS-c moves into the cell nucleus and changes the activity of genes, including antioxidant defence genes.

That last finding is notable because it shows communication running from the mitochondrial genome to the nuclear genome, rather than only the other way round.

Why Muscle Matters

Skeletal muscle is the body's largest user of glucose, and it appears to be the main target of MOTS-c. Mouse studies found the strongest effects on muscle metabolism, and in people, blood and muscle levels have been reported to rise after exercise.

A Natural Genetic Variant

Some people of East Asian ancestry carry a mitochondrial DNA variant that swaps one amino acid in MOTS-c, changing the lysine at position 14 to glutamine (K14Q). Lab tests suggest this version is less active, and it has been linked with both diabetes risk and muscle fibre type.

Key Points

• MOTS-c is a 16-amino-acid peptide coded by mitochondrial DNA.
• It activates the energy sensor AMPK through the folate cycle and AICAR.
• It can enter the nucleus and influence genes under stress.
• Its main target seems to be skeletal muscle.