mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission
Nuria Martinez-Lopez1,2,3,4, Pamela Mattar1,3, Miriam Toledo3,5
1Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Nature Cell Biology
|June 29, 2023
Summary
Fasting activates mTORC2, which phosphorylates NDRG1 to promote mitochondrial fission and maintain respiration. This pathway is crucial for cellular adaptation during nutrient deprivation.
Area of Science:
- Cellular Biology
- Metabolism
- Mitochondrial Dynamics
Background:
- Fasting induces physiological changes, including increased fatty acids and mitochondrial respiration, essential for survival.
- Mechanisms governing mitochondrial adaptation and respiratory function during fasting are not fully understood.
Purpose of the Study:
- To elucidate the role of mTORC2 signaling in regulating mitochondrial function during fasting.
- To identify key proteins and pathways involved in fasting-induced mitochondrial adaptations.
Main Methods:
- Utilized time-lapse imaging to observe mitochondrial dynamics.
- Employed proteomics and small interfering RNA screening.
- Conducted epistasis experiments to determine pathway interactions.
Main Results:
- Fasting and lipid availability stimulate mammalian target of rapamycin complex 2 (mTORC2) activity.
- Activated mTORC2 phosphorylates NDRG1 (NMYC downstream regulated gene 1) at serine 336, sustaining mitochondrial fission.
- Phosphorylated NDRG1 interacts with mitochondria, promoting fission in a DRP1-independent manner, and cooperates with CDC42 (cell division control protein 42) signaling.
Conclusions:
- mTORC2-mediated phosphorylation of NDRG1 is critical for maintaining mitochondrial fission and respiratory sufficiency during fasting.
- The mTORC2-NDRG1-CDC42 axis orchestrates mitochondrial fission, a key adaptation to nutrient scarcity.
- Unexpectedly, mTORC2 reactivates during fasting to drive mitochondrial fission and respiration, contrasting its anabolic role during nutrient surplus.
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