Cellular ATP demand creates metabolically distinct subpopulations of mitochondria Journal Article
| 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. |
| Article Title: | Cellular ATP demand creates metabolically distinct subpopulations of mitochondria |
| 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. © The Author(s), under exclusive licence to Springer Nature Limited 2024. |
| Keywords: | immunohistochemistry; controlled study; human tissue; unclassified drug; gene cluster; human cell; flow cytometry; cell proliferation; reproducibility; electron microscopy; metabolism; protein protein interaction; mitochondrial membrane potential; in vivo study; immunofluorescence; enzyme activity; biosynthesis; amino acid sequence; genetic transfection; western blotting; cell subpopulation; gene fusion; immunoprecipitation; plasmid; mesenchymal stem cell; amino acid; oxidative stress; drosophila melanogaster; adenosine triphosphate; cytokeratin; mass fragmentography; stroma cell; glutamic acid; oxygen consumption; bioenergy; mitochondrion; oxidative phosphorylation; ornithine; proline; biotinylation; enzyme; cell; citric acid cycle; mitochondrial respiration; nutrient availability; subpopulation; gene ontology; respiratory chain; liquid chromatography-mass spectrometry; polyamine; dynamin; putrescine; auxotrophy; fluorescence intensity; proton transporting adenosine triphosphate synthase; carbon metabolism; human; article; mitochondrial fission; mitochondrial dynamics; live cell imaging; oxygen consumption rate; hek293t cell line; cell proliferation assay; respiratory capacity; pyrroline 5 carboxylate synthase |
| Journal Title: | Nature |
| Volume: | 635 |
| Issue: | 8039 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-11-21 |
| Start Page: | 746 |
| End Page: | 754 |
| Language: | English |
| DOI: | 10.1038/s41586-024-08146-w |
| PUBMED: | 39506109 |
| PROVIDER: | scopus |
| PMCID: | PMC11869630 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK author is Craig B. Thompson -- Source: Scopus |
