Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Los Angeles, CA, USA.
Nat Cell Biol. 2023 Jul;25(7):989-1003. doi: 10.1038/s41556-023-01163-3. Epub 2023 Jun 29.
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 NDRG1 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, NDRG1 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.
禁食会引发多种生理适应，包括循环脂肪酸和线粒体呼吸的增加，以促进机体生存。在禁食期间驱动线粒体适应和呼吸充足的机制仍不完全清楚。在这里，我们表明禁食或脂质可用性会刺激 mTORC2 活性。mTORC2 的激活及其下游靶标 NDRG1 的丝氨酸 336 位磷酸化维持线粒体裂变和呼吸充足。延时成像显示，NDRG1（而非磷酸化缺陷型 NDRG1 突变体）与线粒体结合，以促进对照细胞以及缺乏 DRP1 的细胞中的裂变。通过蛋白质组学、小干扰 RNA 筛选和上位性实验，我们表明 mTORC2 磷酸化的 NDRG1 与小 GTPase CDC42 及其 CDC42 的效应物和调节剂合作，协调裂变。因此，Rictor、NDRG1 突变体和 Cdc42 缺陷细胞均表现出类似于裂变失败的线粒体表型。在营养过剩时，mTOR 复合物发挥合成代谢功能；然而，在禁食期间出人意料地重新激活 mTORC2 会驱动线粒体裂变和呼吸。
