What is the difference between MOTS-c and SS-31?

Both peptides engage mitochondrial biology, but from opposite conceptual directions. MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial 12S ribosomal RNA gene — the peptide itself is a product of the mitochondrial genome, one of a young class called mitochondrial-derived peptides (MDPs). It functions as a retrograde signal from the mitochondrion outward, activating AMPK in skeletal muscle to drive improvements in glucose uptake, insulin sensitivity, and (in aged mice, Reynolds 2021 Nature Communications) exercise capacity.

SS-31 (elamipretide) is a synthetic tetrapeptide (D-Arg-2',6'-dimethyl-Tyr-Lys-Phe-NH2) designed by Hazel Szeto and Peter Schiller at Cornell. Its distinctive property is that it concentrates roughly 1000-fold against the electrical gradient into the inner mitochondrial membrane, where it binds cardiolipin — the phospholipid that stabilises cristae architecture. That structural stabilisation preserves electron-transport-chain supercomplex assembly. SS-31 is FDA-approved as Forzinity for Barth syndrome (a rare X-linked disorder of the cardiolipin remodelling enzyme tafazzin).

The two peptides are complementary rather than competitive in mechanism. MOTS-c signals; SS-31 stabilises structure. They target different aspects of mitochondrial biology and could in principle be used together, though no clinical evidence supports the specific combination. On evidence tier, SS-31 has an approved indication and phase-3 human data in Barth; MOTS-c remains without a completed phase-2 or phase-3 interventional human trial for exogenous administration.