Mitochondrial Perturbations Couple mTORC2 to Autophagy in C. elegans

Cell Rep. 2019 Nov 5;29(6):1399-1409.e5. doi: 10.1016/j.celrep.2019.09.072.

Abstract

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.

Keywords: ROS; SGK-1; autophagy; mTOR; mTORC2; mammalian target of rapamycin; mitochondria; mitophagy; reactive oxygen species; serum glucocorticoid-regulated kinase 1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / embryology
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Mechanistic Target of Rapamycin Complex 2 / genetics
  • Mechanistic Target of Rapamycin Complex 2 / metabolism*
  • Mitochondria / metabolism*
  • Mitophagy / genetics*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Rapamycin-Insensitive Companion of mTOR Protein / genetics
  • Rapamycin-Insensitive Companion of mTOR Protein / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / genetics

Substances

  • Caenorhabditis elegans Proteins
  • Forkhead Transcription Factors
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Reactive Oxygen Species
  • daf-16 protein, C elegans
  • rict-1 protein, C elegans
  • Mechanistic Target of Rapamycin Complex 2
  • Protein Serine-Threonine Kinases
  • Sgk-1 protein, C elegans