Mitochondrial-derived peptides (MDPs) are bioactive peptides encoded in mtDNA (within 12S/16S rRNA + the ND open reading frames). They function as cell signaling molecules in glucose homeostasis, apoptosis, and oxidative stress. MOTS-c (16-aa from mt-12S) — exercise mimetic; AMPK activator; declines with age; correlates with metabolic health. Humanin (24-aa from mt-16S) — antiapoptotic; receptor FPRL1/CNTFR/IL-27R. SHLP1-6 family (small humanin-like peptides) — same locus, different reading frames. SS-31 (Bendavia/elamipretide) — synthetic aromatic-cationic tetrapeptide targeting cardiolipin in inner mt membrane → preserves cristae structure under stress; phase 2 trials in primary mitochondrial myopathies + dry AMD + HF (mixed outcomes). Adropin — secreted peptide modulating insulin signaling; gut-liver-brain axis.
Organ Systems
musculoskeletal
endocrine
Pathway Steps
mitochondrial-stress → mdp-secretion — via mtDNA encoded ORFs → translated peptides → cellular signaling beyond traditional nuclear DNA. Mitochondria encode small bioactive peptides — mitochondrial-derived peptides (MDPs) such as humanin and MOTS-c — within their rRNA genes, released under metabolic stress. Acting as hormone-like signals (MOTS-c promotes metabolic homeostasis and exercise adaptation), they form a mitochondria-to-systemic communication axis of growing interest in aging.
Known Modulators
mots c (activator) — AMPK (exercise-mimetic from mt-12S). glucose homeostasis + exercise tolerance + bone density signal; declines with age
humanin (inhibitor) — apoptosis (FPRL1/STAT3-mediated). 24-aa MDP; antiapoptotic; AD plaque neuroprotection claim; analog HNG ~1000× potency