Cellular ATP demand creates metabolically distinct subpopulations of mitochondria

• 成果类型: Article
• 署名作者: Ryu, Keun Woo; Fung, Tak Shun; Baker, Daphne C.; Saoi, Michelle; Park, Jinsung; Febres-Aldana, Christopher A.; Aly, Rania G.; Cui, Ruobing; Sharma, Anurag; Fu, Yi; Jones, Olivia L.; Cai, Xin; Pasolli, H. Amalia; Cross, Justin R.; Rudin, Charles M.; Thompson, Craig B.
• 署名单位: Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Rockefeller University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5110
• DOI: 10.1038/s41586-024-08146-w
• 发表日期: 2024-11-21
• 关键词: absolute quantification; complementation; bioenergetics; DYNAMICS; chain

摘要

Mitochondria serve a crucial role in cell growth and proliferation by supporting both ATP synthesis and the production of macromolecular precursors. Whereas oxidative phosphorylation (OXPHOS) depends mainly on the oxidation of intermediates from the tricarboxylic acid cycle, the mitochondrial production of proline and ornithine relies on reductive synthesis1. How these competing metabolic pathways take place in the same organelle is not clear. Here we show that when cellular dependence on OXPHOS increases, pyrroline-5-carboxylate synthase (P5CS)-the rate-limiting enzyme in the reductive synthesis of proline and ornithine-becomes sequestered in a subset of mitochondria that lack cristae and ATP synthase. This sequestration is driven by both the intrinsic ability of P5CS to form filaments and the mitochondrial fusion and fission cycle. Disruption of mitochondrial dynamics, by impeding mitofusin-mediated fusion or dynamin-like-protein-1-mediated fission, impairs the separation of P5CS-containing mitochondria from mitochondria that are enriched in cristae and ATP synthase. Failure to segregate these metabolic pathways through mitochondrial fusion and fission results in cells either sacrificing the capacity for OXPHOS while sustaining the reductive synthesis of proline, or foregoing proline synthesis while preserving adaptive OXPHOS. These findings provide evidence of the key role of mitochondrial fission and fusion in maintaining both oxidative and reductive biosyntheses in response to changing nutrient availability and bioenergetic demand. Mitochondria are able to maintain two competing metabolic pathways-oxidative phosphorylation and the reductive synthesis of proline and ornithine-by generating two mitochondrial subpopulations that are enriched in either pyrroline-5-carboxylate synthase or ATP synthase.