TORC2-SGK-1 signaling integrates external signals to regulate autophagic turnover of mitochondria via mtROS

Abstract

Macroautophagy/autophagy is an evolutionarily conserved cellular degradation and recycling process that is tightly regulated by external stimuli, diet, and stress. Our recent findings suggest that in C. elegans, a nutrient sensing pathway mediated by MTORC2 (mechanistic target of rapamycin kinase complex 2) and its downstream effector kinase SGK-1 (serum- and glucocorticoid-inducible kinase homolog 1) suppresses autophagy, involving mitophagy. Induced autophagy/mitophagy in MTORC2-deficient animals slows down development and impairs reproduction independently of the SGK-1 effectors DAF-16/FOXO and SKN-1/NFE2L2/NRF2. In this punctum, we discuss how TORC2-SGK-1 signaling might regulate autophagic turnover and its impact on mitochondrial homeostasis via linking mitochondria-derived reactive oxygen species (mtROS) production to mitophagic turnover.

Keywords: Autophagy; MTORC (mechanistic target of rapamycin kinase complex); ROS (reactive oxygen species); SGK-1 (serum- and glucocorticoid-inducible kinase homolog 1); VDAC1 (voltage dependent anion channel 1); mitophagy.

Figure 1.

Loss of sgk-1 or rict-1 induces mitochondrial ROS, resulting in mitophagy. Insert: Simplified model of the regulatory network of SGK-1. SGK-1 phosphorylation and activity is modulated by nutrients and stress via INS-IGF signaling (via the receptor DAF-2) and the MTORC2/RICT-1 complex. SGK-1 has also been proposed to be phospho-regulated by temperature (not shown). SGK-1 negatively controls the transcription factors DAF-16 and SKN-1 involved in lifespan and stress responses. A number of SGK-1 substrates have been proposed, but only one candidate target, the mitochondrial outer membrane protein VDAC-1, is displayed.