Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland.
Department of Biomedical and Medical Sciences, Queen's University, Kingston, Canada.
Cell Rep. 2022 Aug 16;40(7):111198. doi: 10.1016/j.celrep.2022.111198.
The relationship between nutrient starvation and mitochondrial dynamics is poorly understood. We find that cells facing amino acid starvation display clear mitochondrial fusion as a means to evade mitophagy. Surprisingly, further supplementation of glutamine (Q), leucine (L), and arginine (R) did not reverse, but produced stronger mitochondrial hyperfusion. Interestingly, the hyperfusion response to Q + L + R was dependent upon mitochondrial fusion proteins Mfn1 and Opa1 but was independent of MTORC1. Metabolite profiling indicates that Q + L + R addback replenishes amino acid and nucleotide pools. Inhibition of fumarate hydratase, glutaminolysis, or inosine monophosphate dehydrogenase all block Q + L + R-dependent mitochondrial hyperfusion, which suggests critical roles for the tricarboxylic acid (TCA) cycle and purine biosynthesis in this response. Metabolic tracer analyses further support the idea that supplemented Q promotes purine biosynthesis by serving as a donor of amine groups. We thus describe a metabolic mechanism for direct sensing of cellular amino acids to control mitochondrial fusion and cell fate.
营养饥饿与线粒体动力学之间的关系还不太清楚。我们发现，面临氨基酸饥饿的细胞表现出明显的线粒体融合，以此来逃避线粒体自噬。令人惊讶的是，进一步补充谷氨酰胺（Q）、亮氨酸（L）和精氨酸（R）不仅没有逆转，反而产生了更强的线粒体超融合。有趣的是，Q+L+R 引起的超融合反应依赖于线粒体融合蛋白 Mfn1 和 Opa1，但不依赖于 MTORC1。代谢物分析表明，Q+L+R 的补充恢复了氨基酸和核苷酸池。延胡索酸水合酶、谷氨酰胺分解或肌苷单磷酸脱氢酶的抑制都阻止了 Q+L+R 依赖的线粒体超融合，这表明三羧酸（TCA）循环和嘌呤生物合成在这一反应中起着关键作用。代谢示踪剂分析进一步支持了这样一种观点，即补充的 Q 通过作为胺基团的供体来促进嘌呤生物合成。因此，我们描述了一种直接感知细胞氨基酸以控制线粒体融合和细胞命运的代谢机制。
