The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index.
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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Cites
Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death
Wei, M. C., Zong, W.-X., Cheng, E. H.-Y., Lindsten, T., Panoutsakopoulou, V., Ross, A. J., Roth, K. A., MacGregor, G. R., Thompson, C. B., & Korsmeyer, S. J. (2001) · Science · doi:10.1126/science.1059108 · Cited by 3,988
Mitofusin 2 tethers endoplasmic reticulum to mitochondria
de Brito, O. M., & Scorrano, L. (2008) · Nature · doi:10.1038/nature07534 · Cited by 2,442
Efficient proximity labeling in living cells and organisms with TurboID
Branon, T. C., Bosch, J. A., Sanchez, A. D., Udeshi, N. D., Svinkina, T., Carr, S. A., Feldman, J. L., Perrimon, N., & Ting, A. Y. (2018) · Nature Biotechnology · doi:10.1038/nbt.4201 · Cited by 2,174
The multifaceted contributions of mitochondria to cellular metabolism
Spinelli, J. B., & Haigis, M. C. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0124-1 · Cited by 1,935
Rath, S., Sharma, R., Gupta, R., Ast, T., Chan, C., Durham, T. J., Goodman, R. P., Grabarek, Z., Haas, M. E., Hung, W. H. W., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkaa1011 · Cited by 1,888
The cell biology of mitochondrial membrane dynamics
Giacomello, M., Pyakurel, A., Glytsou, C., & Scorrano, L. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0210-7 · Cited by 1,550
Bcl-xL Regulates the Membrane Potential and Volume Homeostasis of Mitochondria
Heiden, M. G. V., Chandel, N. S., Williamson, E. K., Schumacker, P. T., & Thompson, C. B. (1997) · Cell · doi:10.1016/s0092-8674(00)80450-x · Cited by 1,378
Cogliati, S., Frezza, C., Soriano, M. E., Varanita, T., Quintana-Cabrera, R., Corrado, M., Cipolat, S., Costa, V., Casarin, A., Gomes, L. C., et al. (2013) · Cell · doi:10.1016/j.cell.2013.08.032 · Cited by 1,265
Kamphorst, J. J., Nofal, M., Commisso, C., Hackett, S. R., Lu, W., Grabocka, E., Vander Heiden, M. G., Miller, G., Drebin, J. A., Bar-Sagi, D., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2211 · Cited by 893
Distinct fission signatures predict mitochondrial degradation or biogenesis.
Kleele, T., Rey, T., Winter, J., Zaganelli, S., Mahecic, D., Perreten Lambert, H., Ruberto, F. P., Nemir, M., Wai, T., Pedrazzini, T., et al. (2021) · Nature · doi:10.1038/s41586-021-03510-6 · Cited by 794
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The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease
Zanfardino, P., Amati, A., Perrone, M., & Petruzzella, V. (2025) · Biomolecules · doi:10.3390/biom15030433 · Cited by 129
“One subpopulation, devoid of cristae but enriched in pyrroline-5-carboxylate synthase (P5CS), supports proline and ornithine biosynthesis, optimizing metabolic flexibility through fusion–fission cycles [42].”
Arginine: at the crossroads of nitrogen metabolism
Fung, T. S., Ryu, K. W., & Thompson, C. B. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00379-3 · Cited by 113
“Instead, recent studies suggest that glutamine is the major source of proline biosynthesis (Ryu et al, 2024; Schwörer et al, 2020; Tran et al, 2021; Zhu et al, 2021).”
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“P5CS activity is enhanced under elevated MMP relative to base-line, promoting the formation of filamentous assemblies of P5CS that drive reductive biosynthesis [38].”
Mitochondrial origins of the pressure to sleep
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“operate continuously to mix and re-compartmentalize mitochondrial content for maintenance or metabolic control 44,45 .”
Liu, X., Luo, Q., Zhao, Y., Ren, P., Jin, Y., & Zhou, J. (2025) · Antioxidants · doi:10.3390/antiox14050613 · Cited by 59
“ATP synthesis is mainly dependent on the oxidative phosphorylation (OXPHOS) pathway in mitochondria [90,91].”
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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