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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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Polyamines in Cancer: Mechanisms, Metabolic Targets, and Therapeutic Opportunities
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“…regulate the balance between OXPHOS and reductive proline biosynthesis by creating distinct mitochondrial subpopulations: one enriched in ATP synthase for OXPHOS, and another enriched in P5CS which prioritizes reductive biosynthesis by suppressing TCA cycle activity and glutamate oxidation [116].”
Proline Metabolism in Cancer: Emerging Roles in Redox Homeostasis and Therapeutic Opportunities
Rossman, T. C., Purohit, G., Daudu, O. I., & Becker, D. (2025) · Cancers · doi:10.3390/cancers17193156 · Cited by 7
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“18 There is growing evidence linking mitochondrial alterations in cancer cells to tumor progression, migration, and chemoresistance, with altered mitochondrial dynamics being a key factor.”
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Therapeutic and mechanistic insights on mitochondrial transplantation in kidney disease
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“A 2024 study 41 showed that when cellular dependence on oxidative phosphorylation increases, pyrroline-5-carboxylate synthase — 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, and…”
Mitotyping – An integrative framework to quantify mitochondrial specialization and plasticityPreprint
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Cells are swapping their mitochondria. What does this mean for our health?
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“17 V-ATPase is a complex composed of multiple subunits, primarily consisting of two domains, the cytosolic V1 domain and the transmembrane V0 domain.”
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The potential of mitochondrial transfer as the modifying therapy for osteoarthritis
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“Mitochondrial functions encompass a range of molecular activities, including amino acid metabolism (Ryu et al., 2024) .”
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“Disruption of mitochondrial dynamics impairs the capacity for ATP generation by OXPHOS or reductive synthesis for cell proliferation 87,90,91 .”
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“As cancer cells, HeLa WT cells have a variety of mitochondria ultrastructure, which has been linked to its ability to adapt to the environment and grow (72).”
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“Within individual cells, mitochondrial subpopulations can meet compartment-specific bioenergetic demands [7].”
Haematometabolism rewiring in atherosclerotic cardiovascular disease
Yvan‐Charvet, L., Barouillet, T., & Borowczyk, C. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-024-01108-9 · Cited by 7
“Of note, cellular ATP demand might create metabolically distinct subpopulations of mitochondria 216 .”
Mitochondrial heterogeneity: subpopulations with distinct metabolic activities
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A dual-purification system to isolate mitochondrial subpopulations
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“With regards to the latter, a recent study has discovered that a subset of mitochondria contains pyrroline-5-carboxylate synthase (P5CS; also known as ALDH18A1) filaments (Ryu et al., 2024).”
InfluentialExploring the oncogenic impact of heteroplasmic de novo MT-ND5 truncating mutations
Wu, Y., Ye, J., & Gu, Z. (2025) · Mitochondrial Communications · doi:10.1016/j.mitoco.2025.03.001 · Cited by 4
“82 This functional diversity may enhance metabolic flexibility, enabling cells to adapt to fluctuating environmental conditions.”
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Mitochondrial NAD + gradient sustained by membrane potential and transport
Goyal, S., Lyons, S. N., & Cambronne, X. A. (2025) · Science Advances · doi:10.1126/sciadv.aea7460 · Cited by 5
“During fission or fusion, an acute loss of ΔΨ m may serve to rapidly and reversibly pause NAD + import ( 53 – 56 ), and this could further occur in microdomains within the organelle ( 57 – 59 ).”
Metabolic Adaptation to Following Temperature Acclimation in Fish on the Yun-Gui Plateau
Dao, W., Long, J., Yin, Y., Wu, A., Chen, Y., Gao, H., Pan, X., Yang, J., Wang, X., & Zhang, Y. (2025) · Biology · doi:10.3390/biology14121645 · Cited by 4
“Mitochondria act as cellular energy ‘powerhouses’, providing approximately 90% of ATP through oxidative phosphorylation (OXPHOS), thus underpinning nearly all animal activities [8,29,30].”
Wang, J., Han, X., Cai, J., Song, R., Li, Z., & Lin, Y. (2025) · Materials Today · doi:10.1016/j.mattod.2025.12.004 · Cited by 4
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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