| FUNDC1 anchors to the mitochondrial outer membrane as an OMM protein that mediates hypoxia-induced mitophagy through direct interaction with LC3 family proteins on forming autophagosomes. The protein features an N-terminal LIR motif with a core W/F/Y-xx-L/I/V sequence flanked by flanking acidic residues that engage LC3 hydrophobic pockets, alongside conserved phosphorylation sites at tyrosine 18, serine 13, and serine 17 that reversibly modulate binding affinity. Under normoxia, Src kinase phosphorylates Tyr18 to disrupt LIR-LC3 interaction while CK2 targets Ser13 to maintain inhibitory conformation, preventing mitophagosome formation; hypoxia inactivates Src and activates PGAM5 phosphatase to dephosphorylate both sites, exposing the LIR for high-affinity LC3/GABARAP binding and Parkin-independent mitochondrial clearance. ULK1/ATG1 kinase phosphorylates Ser17 during starvation to further enhance LC3 association and autophagosome engulfment, while MARCH5 E3 ligase ubiquitinates lysine residues under steady state to target FUNDC1 for proteasomal degradation via the cytosol-to-mitochondria import pathway. FUNDC1 coordinates with Drp1 to regulate mitochondrial fission at ER-mitochondria contact sites through Tyr18 dephosphorylation, balancing fusion-fission dynamics during metabolic stress. The protein forms a tripartite complex with PGAM5 and CK2α to create a hypoxia-responsive switch that integrates kinase-phosphatase signaling with LC3 lipidation cascades. FUNDC1 deficiency impairs hypoxic adaptation in cardiomyocytes and hepatocytes, leading to mitochondrial accumulation and ROS-mediated damage. Phosphomimetic mutants at Ser13/17 block mitophagy induction, while non-phosphorylatable Tyr18 variants constitutively activate clearance. |
Lane 1: RAW264.7, Lane 2: C6, Lane 3: H-4-II-E
