Cellular ATP demand creates metabolically distinct subpopulations of mitochondria

Keun Woo Ryu, Tak Shun Fung, Daphne C. Baker, Michelle Saoi, Jinsung Park, Christopher A. Febres-Aldana, Rania G. Aly, Ruobing Cui, Anurag Sharma, Yi Fu, Olivia L. Jones, Xin Cai, H. Amalia Pasolli, Justin R. Cross, Charles M. Rudin and Craig B. Thompson ()
Additional contact information
Keun Woo Ryu: Memorial Sloan Kettering Cancer Center
Tak Shun Fung: Memorial Sloan Kettering Cancer Center
Daphne C. Baker: Memorial Sloan Kettering Cancer Center
Michelle Saoi: Memorial Sloan Kettering Cancer Center
Jinsung Park: Memorial Sloan Kettering Cancer Center
Christopher A. Febres-Aldana: Memorial Sloan Kettering Cancer Center
Rania G. Aly: Memorial Sloan Kettering Cancer Center
Ruobing Cui: Memorial Sloan Kettering Cancer Center
Anurag Sharma: The Rockefeller University
Yi Fu: Memorial Sloan Kettering Cancer Center
Olivia L. Jones: Memorial Sloan Kettering Cancer Center
Xin Cai: Memorial Sloan Kettering Cancer Center
H. Amalia Pasolli: The Rockefeller University
Justin R. Cross: Memorial Sloan Kettering Cancer Center
Charles M. Rudin: Memorial Sloan Kettering Cancer Center
Craig B. Thompson: Memorial Sloan Kettering Cancer Center

Nature, 2024, vol. 635, issue 8039, 746-754

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-08146-w

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