Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance

AMP-activated protein kinase (AMPK) plays a central role in cellular energy sensing and bioenergetics. However, the role of AMPK in surveillance of mitochondrial damage and induction of mitophagy remains unclear. We demonstrate herein that AMPK is required for efficient mitophagy. Mitochondrial damage induces a physical association of AMPK with ATG16-ATG5-12 and an AMPK-dependent recruitment of the VPS34 and ATG16 complexes with the mitochondria. Targeting AMPK to the mitochondria is both sufficient to induce mitophagy and to promote cell survival. Recruitment of AMPK to the mitochondria requires N-myristoylation of AMPKβ by the type-I N-myristoyltransferase 1 (NMT1). Our data support a spatiotemporal model wherein recruitment of AMPK in association with components of the VPS34 and ATG16 complex to damaged mitochondria regulates selective mitophagy to maintain cancer cell viability. AMP-activated protein kinase (AMPK) plays a role in starvation-induced autophagy, but a role in mitochondrial damage-induced mitophagy is not known. Here, Liang et al. show that AMPK is recruited to damaged mitochondria in an N-myristoylation-dependent manner and in turn recruits the ATG16 autophagy complex.