Category: cell_death
Mitophagy — selective autophagy of damaged mitochondria — distinct from general macroautophagy ([[autophagy_lc3_axis]]). Quality-control mechanism preventing accumulation of dysfunctional mitochondria. Canonical PINK1/Parkin pathway: (1) Healthy mitochondria — PINK1 (PTEN-induced kinase 1) is imported through TOM/TIM complexes to the inner membrane → MPP-cleaved → degraded. PINK1 levels stay low. (2) Damaged mitochondria — loss of inner-membrane potential (Δψm) blocks PINK1 import → PINK1 accumulates on the outer membrane (OMM) → activates by trans-autophosphorylation → phosphorylates ubiquitin Ser65 + Parkin. (3) Parkin recruitment + amplification — pSer65-Ub binds + activates Parkin (an E3 ubiquitin ligase) → Parkin polyubiquitinates OMM proteins (Mfn1/2, MIRO1/2, TOM20) → more pSer65-Ub → feed-forward loop. (4) Autophagy receptors — OPTN, NDP52, TAX1BP1, p62 bind polyubiquitin chains → LC3 recruitment → autophagosome enclosure → lysosomal fusion → degradation. PINK1/Parkin-independent mitophagy: BNIP3, NIX, FUNDC1 are receptors that bind LC3 directly (no ubiquitin step) — important for developmental mitophagy (erythrocyte maturation, hypoxia response). Disease relevance: PINK1 + PRKN (Parkin) loss-of-function mutations → autosomal recessive early-onset Parkinson disease (cross-link [[parkinson_alpha_synuclein_aggregation]] — failure of dopaminergic mitochondrial QC). Therapeutic landscape: urolithin A (a gut-microbiome metabolite of ellagic acid) is the first compound demonstrated to induce mitophagy in humans (MIBIOTECH trial); rapamycin + metformin enhance mitophagy via AMPK + mTORC1; NAD precursors (NMN, NR) support PARP/SIRT axis. Cross-links: [[autophagy_lc3_axis]] (parent autophagy mechanism), [[parkinson_alpha_synuclein_aggregation]] (PINK1/PRKN loss → familial PD), [[ampk_signaling]] (mitophagy induction via energy stress), [[mtor_signaling]] (mTORC1 inhibition promotes mitophagy).