Hypoxia-induced MIC19 myristoylation promotes PRKN-dependent VDAC2 ubiquitination and activates mitophagy in non-small cell lung cancer.

Tumor hypoxia drives mitophagy reprogramming to support mitochondrial quality control in non-small cell lung cancer (NSCLC) cells, yet the role of the mitochondrial cristae organizers remains poorly understood. Here, we identified MIC19, a key subunit of mitochondrial contact site and cristae organizing system complex, as an essential regulator of hypoxia-induced mitophagy in NSCLC. We demonstrate that prolonged hypoxia induces MIC19 protein expression in a HIF-1α-dependent manner and that elevated MIC19 promotes NSCLC cell proliferation and metastasis. MIC19 sustains mitochondrial morphology and mitophagy activation under hypoxic stress. Mechanistically, HIF-1α transcriptionally upregulates NMT1, an N-myristoyltransferase that catalyzes N-myristoylation at Gly2 of MIC19 protein, which is essential for the mitochondrial localization and protein stability of MIC19. MIC19 facilitates PRKN-dependent K48-linked ubiquitination of the outer mitochondrial membrane protein voltage-dependent anion channel 2 (VDAC2), thereby promoting mitophagy progression under hypoxic stress. Therapeutically, suppression of MIC19 via shRNA combined with pharmacological inhibition of autophagy using chloroquine synergistically impairs NSCLC tumor growth in vivo. Collectively, these findings uncover a previously unrecognized HIF-1α-NMT1-MIC19-VDAC2 axis that drives hypoxia-adaptive mitophagy and reveals a potential therapeutic vulnerability in hypoxic NSCLC.