Mitochondrial-derived peptide signaling

Mitochondria contain their own genome (mtDNA), which encodes 13 proteins, 22 tRNAs, 2 rRNAs — and, remarkably, several small peptides with signaling functions. MOTS-c (16 aa, from 12S rRNA) and Humanin (24 aa, from 16S rRNA) are the best characterized. MOTS-c activates AMPK and translocates to the nucleus under metabolic stress, regulating adaptive gene expression. Humanin protects against apoptosis via Bax inhibition. Both represent a paradigm shift: mitochondria are not just powerhouses but signaling organelles. SS-31 (Elamipretide) takes a different approach — it's a synthetic tetrapeptide that targets cardiolipin in the inner mitochondrial membrane, stabilizing respiratory supercomplexes.