Mitochondrial Perturbations Couple mTORC2 to Autophagy in C. elegans

Abstract

Summary: Autophagy is stimulated by stress conditions and needs to be precisely tuned to ensure cellular homeostasis and organismal development and health. The kinase mechanistic target of rapamycin (mTOR) forms the enzymatic core of the highly conserved mTOR complexes mTORC1 and mTORC2. mTORC1 is a key inhibitor of autophagy, yet the function of mTORC2 in autophagy is controversial. We here show that inactivation of mTORC2 and its direct target serum- and glucocorticoid-inducible kinase 1 (SGK-1) potently induces autophagy and the autophagic degradation of mitochondria in C. elegans. Enhanced autophagy in mTORC2- or SGK-1-deficient animals contributes to their developmental and reproductive defects and is independent of the canonical SGK-1 effector DAF-16/FOXO. Importantly, we find that inactivation of mTORC2-SGK-1 signaling impairs mitochondrial homeostasis and triggers an increased release of mitochondria-derived reactive oxygen species (mtROS) to induce autophagy. Thus, mitochondrial stress couples reduced mTORC2 activity to enhanced autophagic turnover. : The multiprotein complex mTORC2 is a central regulator of development and metabolism. Aspernig et al. implicate C. elegans mTORC2 and its effector SGK-1 in mitochondrial homeostasis and report that an increased release of mitochondria-derived reactive oxygen species induces autophagy in mTORC2/SGK-1-deficient animals. Keywords: mammalian target of rapamycin, mTOR, mTORC2, serum glucocorticoid-regulated kinase 1, SGK-1, autophagy, mitophagy, mitochondria, reactive oxygen species, ROS