RT Journal Article
SR Electronic
T1 mTORC2 couples fasting to mitochondrial fission
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.07.19.500669
DO 10.1101/2022.07.19.500669
A1 Nuria Martinez-Lopez
A1 Pamela Mattar
A1 Miriam Toledo
A1 Henrietta Bains
A1 Manu Kalyani
A1 Marie Louise Aoun
A1 Mridul Sharma
A1 Laura Beth J. McIntyre
A1 Leslie Gunther-Cummins
A1 Frank P. Macaluso
A1 Jennifer T. Aguilan
A1 Simone Sidoli
A1 Mathieu Bourdenx
A1 Rajat Singh
YR 2022
UL http://biorxiv.org/content/early/2022/07/20/2022.07.19.500669.abstract
AB Fasting triggers diverse cellular and metabolic adaptations to facilitate organismal survival1,2. During nutrient deprivation, increases in circulating fatty acids support mitochondrial respiration2. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during nutrient deprivation remain incompletely understood. Here we show that extended periods of fasting, or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its target NDRG13 at S336 sustains mitochondrial fission and respiratory sufficiency. Timelapse imaging reveals that wildtype NDRG1, but not phosphorylation-deficient NDRG1S336A mutant, engages with mitochondria to facilitate its scission. Using proteomics, and an siRNA screen, we show that mTORC2-phosphorylated NDRG1 cooperates with the small GTPase Cdc424 and Cdc42-specific effectors and regulators to orchestrate fission. Accordingly, RictorKO, NDRG1S336A mutants, and Cdc42-deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions5; however, paradoxical reactivation of mTORC2 during fasting plays an unexpected role in driving mitochondrial fission and respiration.Competing Interest StatementThe authors have declared no competing interest.