美国纪念斯隆凯特琳癌症研究所Craig B. Thompson团队发现，细胞的ATP需求创造出代谢上不同的线粒体亚群。该研究于2024年11月6日在线发表于国际一流学术期刊《自然》。

研究人员发现，当细胞对氧化磷酸化（OXPHOS）的依赖性增加时，脯氨酸-5-羧酸合成酶（P5CS），即脯氨酸和鸟氨酸还原合成的限速酶，会被隔离到一个缺乏嵴和ATP合酶的线粒体亚群中。这一隔离现象是由P5CS自身能够形成丝状结构的特性以及线粒体的融合和分裂周期共同驱动的。

通过阻止Mitofusin介导的融合或动力蛋白1（DLP1）介导的分裂，线粒体动力学受到干扰，从而影响了含P5CS的线粒体与富含嵴和ATP合酶的线粒体的分离。当这些代谢途径无法通过线粒体的融合和分裂得到有效隔离时，细胞要么牺牲OXPHOS的能力，同时维持脯氨酸的还原合成，要么放弃脯氨酸合成，同时保留适应性的OXPHOS。

这些发现为线粒体分裂和融合在应对营养可用性和生物能需求变化时维持氧化和还原生物合成的关键作用提供了证据。

据了解，线粒体在细胞生长和增殖中起着至关重要的作用，通过支持ATP合成和大分子前体的生产来维持细胞功能。尽管OXPHOS主要依赖于三羧酸循环中间体的氧化，但线粒体中脯氨酸和鸟氨酸的合成则依赖于还原性合成。然而，这些竞争性的代谢途径，如何在同一个细胞器内进行尚不清楚。

附：英文原文

Title: Cellular ATP demand creates metabolically distinct subpopulations of mitochondria

Author: 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.

Issue&Volume: 2024-11-06

Abstract: 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.

DOI: 10.1038/s41586-024-08146-w

Source: https://www.nature.com/articles/s41586-024-08146-w