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mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission

Martinez-Lopez, Nuria; Mattar, Pamela; Toledo, Miriam; Bains, Henrietta; Kalyani, Manu; Aoun, Marie Louise; Sharma, Mridul; ... Singh, Rajat; + view all (2023) mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission. Nature Cell Biology , 25 (7) pp. 989-1003. 10.1038/s41556-023-01163-3. Green open access

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Abstract

Fasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at serine 336 sustains mitochondrial fission and respiratory sufficiency. Time-lapse imaging shows that NDRG1, but not the phosphorylation-deficient NDRG1Ser336Ala mutant, engages with mitochondria to facilitate fission in control cells, as well as in those lacking DRP1. Using proteomics, a small interfering RNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase CDC42 and effectors and regulators of CDC42 to orchestrate fission. Accordingly, Rictor KO, NDRG1Ser336Ala mutants and Cdc42-deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.

Type: Article
Title: mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41556-023-01163-3
Publisher version: http://dx.doi.org/10.1038/s41556-023-01163-3
Language: English
Additional information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell Biology, CDC42 PROTEIN, PHOSPHORYLATION, MTORC2, AUTOPHAGY, COMPLEX, DRP1, METABOLISM, PROTEOMICS, MEMBRANES, IQGAP1
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10186900
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