Mitochondrial-derived peptides: emerging therapeutic targets at the intersection of mitochondrial dysfunction and pain

Mitochondrial-derived peptides (MDPs), including humanin and MOTS-c, are endogenous peptide signaling molecules that regulate cellular stress responses and metabolic homeostasis. Mitochondrial dysfunction is a convergent downstream mechanism across diverse chronic pain states, yet existing therapies target only limited neural mechanisms. Recent preclinical evidences demonstrate that humanin and MOTS-c exert analgesic effects across multiple pain models through shared mechanisms converging on AMPK-PGC-1α-mediated mitochondrial biogenesis and suppression of oxidative stress and neuroinflammation. Humanin attenuates metabolic, toxic, and traumatic neuropathic pain while reducing pain-related markers in dorsal root ganglia. MOTS-c shows broader efficacy across neuropathic, diabetic, inflammatory, and cancer-induced bone pain models, with mechanistic evidence linking its effects to AMPK activation, microglial inhibition, and restoration of mitochondrial function. Endogenous MDP levels decline in pain states, suggesting that their loss contributes to pain pathogenesis and that restoration may be therapeutic. SHLPs, particularly SHLP2, have not been directly studied in pain but exhibit anti-inflammatory and anti-apoptotic properties that provide a plausible indirect link. This review synthesizes current evidence on MDPs in pain, and proposes priorities for translating these endogenous peptides into therapeutic strategies for chronic pain.