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Cellular ATP demand creates metabolically distinct subpopulations of mitochondria
Open accessAbstract
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 synthesis 1. 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.
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“Recently, it has been reported that starving cells can overcome the difficulty of balancing catabolic and anabolic processes using the fusion and fission cycle to sequester a subset of mitochondria specialized on synthetic processes instead of oxidative phosphorylation [102].”
From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [102]
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Metadata
- Authors
- Ryu, K. W., Fung, T. S., Baker, D. C., Saoi, M., Park, J., Febres-Aldana, C. A., Aly, R. G., Cui, R., Sharma, A., Fu, Y., Jones, O. L., Cai, X., Pasolli, H. A., Cross, J. R., Rudin, C. M., & Thompson, C. B.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Rockefeller University (US)
- Corresponding author
- Thompson, Craig B.
- ORCID
- Venue
- Nature
- Published
- 2024-11-06
- Volume
- 635
- Issue
- 8039
- Pages
- 746-754
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC11869630
- OpenAlex
- W4404105362
- Cited by
- 284
- References
- 43
- Citations by year
- 2026: 125 · 2025: 154 · 2024: 5
- FWCI
- 38.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Memorial Sloan-Kettering Cancer Center (CA008748, P30 CA008748)
- National Cancer Institute (K99CA256505, CA008748, CA263816, P30CA008748, R35CA283988, R35CA263816)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- mitochondrial heterogeneity, mitochondrial subpopulations, pyrroline-5-carboxylate synthase, proline biosynthesis, ornithine biosynthesis, oxidative phosphorylation, ATP synthase, mitochondrial fusion, mitochondrial fission, mitofusins, Drp1, mitochondrial cristae, ATP demand, metabolic compartmentation
- MeSH terms
- Adenosine Triphosphate, Animals, Cell Line, Humans, Mitochondria, Ornithine, Ornithine-Oxo-Acid Transaminase, Oxidative Phosphorylation, Proline, Carbon-Nitrogen Ligases, GTP Phosphohydrolases, Mitochondrial Proteins, Mitochondrial Proton-Translocating ATPases, Dynamins, Mice, Mitochondrial Dynamics
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