MOTS-c

MOTS-c is a sixteen-amino-acid peptide, and the remarkable thing about it is where its instructions are kept. It is encoded not in the nucleus, where essentially all of a cell's genes live, but in the small circular genome carried by mitochondria themselves.

Mitochondria were once free-living bacteria, absorbed into another cell more than a billion years ago, and they still carry a remnant of their own DNA. For decades that remnant was understood to encode thirteen proteins, all of them components of the machinery that generates energy. The discovery that it also encodes short signalling peptides was genuinely unexpected.

MOTS-c is the best characterised of them. Its sequence is hidden inside the gene for a mitochondrial ribosomal RNA — the same stretch of DNA read one way produces the RNA and read another produces this peptide. It travels out of the mitochondrion, and under stress it moves into the nucleus and influences which nuclear genes are read. A signal sent from the organelle to the cell's own control centre is a striking inversion of the usual direction of command.

• A message from the mitochondria: Communication normally runs from nucleus to organelle. A peptide encoded in mitochondrial DNA that relocates to the nucleus reverses that, and establishes the mitochondrion as a source of instructions rather than only a recipient.

• AMPK activation: It is reported to activate the cell's main energy sensor, connecting it to the same pathway that responds to fuel shortage and to exercise.

• Responsive to exercise: Concentrations rise with physical activity in published human measurements, which is unusual: most compounds in this category have no established natural fluctuation to anchor them.

• Coding within coding: Its sequence sits inside a gene for something else entirely. That a small genome stores information at two levels at once is a significant finding about genome organisation.

A mitochondrion is not simply a power station taking orders. It has its own small genome, its own protein-making machinery, and — as this peptide shows — its own way of reporting upward. When mitochondrial conditions change, the cell has to know, because almost everything it does depends on its energy supply.

MOTS-c appears to be one of those reports. Under metabolic stress it accumulates in the nucleus, where it associates with transcription factors and influences genes involved in antioxidant defence and metabolic adjustment. The mitochondrion is, in effect, asking the nucleus to change what it produces.

Its other reported action is on AMPK, the enzyme that monitors a cell's energy state and shifts it from spending to earning. Published work also connects it to the folate cycle, which supplies the one-carbon units used in a great deal of biosynthesis. The picture is of a peptide operating at the junction between energy availability and what the cell chooses to build — which is exactly what a signal from the mitochondria would be expected to do.

The core discovery is solid and independently significant. That mitochondrial DNA encodes short peptides, that MOTS-c is one of them, and that it relocates to the nucleus under stress are published in peer-reviewed journals and have been taken up widely. Human measurements showing concentrations rise with exercise add a useful anchor.

Functional work is mostly cell culture and mouse studies, and the field is young — the peptide was described in 2015. There is no approved use and it is supplied for laboratory research only. The fundamental finding is secure and significant: mitochondrial DNA encodes short signalling peptides, and this is the best characterised of them.

SS-31 is the natural companion: both concern mitochondria, one as a signal originating there and the other as a molecule acting on the structure of the membranes. Signal against structure is the useful distinction.

NAD+ is the coenzyme most mitochondrial chemistry runs on, and AICAR activates the same energy sensor by imitating a low-energy state — a chemical route to a signal this peptide appears to carry naturally.