1932
0

Annual Review of Cancer Biology

Volume 9, 2025

Distinct Essentiality of the Mitochondrial Respiratory Chain in Proliferating Cells In Vivo

  • Claudie Bosc1 and Navdeep S. Chandel1
  • Departments of Medicine and Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; email: [email protected]
  • Vol. 9:59-77 (Volume publication date April 2025)
  • First published as a Review in Advance on October 30, 2024
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

Mitochondrial respiratory chain (RC) activity is essential for in vivo cell proliferation, particularly in cancer, CD4+ and CD8+ T cells, and endothelial cells involving ATP production and biosynthesis. The RC is essential for the oxidative tricarboxylic acid (TCA) cycle to produce intermediates that funnel into anabolic pathways to synthesize lipids, proteins, and nucleotides. By contrast, mitochondrial respiration has a distinct role in other proliferating cells including regulatory T cells (Tregs) and stem cells whereby mitochondria are dispensable for in vivo cell proliferation but determine cell fate and function through several signaling mechanisms. In this review, we discuss how the mitochondrial RC is an anabolic engine that supports the proliferation of cancer cells, CD4+ and CD8+ T cells, and endothelial cells while mitochondria serve as central hubs that integrate metabolic signals to control Treg and stem cell fate and function in vivo.

Keyword(s): cancer cells, endothelial cells, metabolites, ROS, stem cells, T cells
Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-061424-125611
2025-04-11
2025-06-13
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/9/1/annurev-cancerbio-061424-125611.html?itemId=/content/journals/10.1146/annurev-cancerbio-061424-125611&mimeType=html&fmt=ahah

Literature Cited

  1. Andrade J, Shi C, Costa ASH, Choi J, Kim J, et al. 2021.. Control of endothelial quiescence by FOXO-regulated metabolites. . Nat. Cell Biol. 23:(4):413–23
     [Crossref] [Google Scholar]
  2. Angelin A, Gil-de-Gómez L, Dahiya S, Jiao J, Guo L, et al. 2017.. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. . Cell Metab. 25:(6):1282–93.e7
     [Crossref] [Google Scholar]
  3. Ansó E, Weinberg SE, Diebold LP, Thompson BJ, Malinge S, et al. 2017.. The mitochondrial respiratory chain is essential for haematopoietic stem cell function. . Nat. Cell Biol. 19:(6):614–25
     [Crossref] [Google Scholar]
  4. Arner EN, Rathmell JC. 2023.. Metabolic programming and immune suppression in the tumor microenvironment. . Cancer Cell 41:(3):421–33
     [Crossref] [Google Scholar]
  5. Asano J, Sato T, Ichinose S, Kajita M, Onai N, et al. 2017.. Intrinsic autophagy is required for the maintenance of intestinal stem cells and for irradiation-induced intestinal regeneration. . Cell Rep. 20:(5):1050–60
     [Crossref] [Google Scholar]
  6. Avgustinova A, Benitah SA. 2016.. Epigenetic control of adult stem cell function. . Nat. Rev. Mol. Cell Biol. 17:(10):643–58
     [Crossref] [Google Scholar]
  7. Bajzikova M, Kovarova J, Coelho AR, Boukalova S, Oh S, et al. 2019.. Reactivation of dihydroorotate dehydrogenase-driven pyrimidine biosynthesis restores tumor growth of respiration-deficient cancer cells. . Cell Metab. 29:(2):399–416.e10
     [Crossref] [Google Scholar]
  8. Baksh SC, Todorova PK, Gur-Cohen S, Hurwitz B, Ge Y, et al. 2020.. Extracellular serine controls epidermal stem cell fate and tumour initiation. . Nat. Cell Biol. 22:(7):779–90
     [Crossref] [Google Scholar]
  9. Bantug GR, Fischer M, Grählert J, Balmer ML, Unterstab G, et al. 2018.. Mitochondria-endoplasmic reticulum contact sites function as immunometabolic hubs that orchestrate the rapid recall response of memory CD8+ T cells. . Immunity 48:(3):542–55.e6
     [Crossref] [Google Scholar]
  10. Bardella C, Pollard PJ, Tomlinson I. 2011.. SDH mutations in cancer. . Biochim. Biophys. Acta Bioenerg. 1807:(11):1432–43
     [Crossref] [Google Scholar]
  11. Bartman CR, Faubert B, Rabinowitz JD, DeBerardinis RJ. 2023.. Metabolic pathway analysis using stable isotopes in patients with cancer. . Nat. Rev. Cancer 23:(12):863–78
     [Crossref] [Google Scholar]
  12. Beier UH, Angelin A, Akimova T, Wang L, Liu Y, et al. 2015.. Essential role of mitochondrial energy metabolism in Foxp3+ T-regulatory cell function and allograft survival. . FASEB J. 29:(6):2315–26
     [Crossref] [Google Scholar]
  13. Bell HN, Stockwell BR, Zou W. 2024.. Ironing out the role of ferroptosis in immunity. . Immunity 57:(5):941–56
     [Crossref] [Google Scholar]
  14. Bezwada D, Lesner NP, Brooks B, Vu HS, Wu Z, et al. 2023.. Mitochondrial metabolism in primary and metastatic human kidney cancers. . bioRxiv 2023.02.06.527285. https://doi.org/10.1101/2023.02.06.527285
  15. Bhattacharya D, Scimè A. 2020.. Mitochondrial function in muscle stem cell fates. . Front. Cell Dev. Biol. 8::480
     [Crossref] [Google Scholar]
  16. Biancur DE, Kapner KS, Yamamoto K, Banh RS, Neggers JE, et al. 2021.. Functional genomics identifies metabolic vulnerabilities in pancreatic cancer. . Cell Metab. 33:(1):199–210.e8
     [Crossref] [Google Scholar]
  17. Bosc C, Saland E, Bousard A, Gadaud N, Sabatier M, et al. 2021.. Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia. . Nat. Cancer 2:(11):1204–23
     [Crossref] [Google Scholar]
  18. Buck MD, O'Sullivan D, Klein Geltink RI, Curtis JD, Chang C-H, et al. 2016.. Mitochondrial dynamics controls T cell fate through metabolic programming. . Cell 166:(1):63–76
     [Crossref] [Google Scholar]
  19. Chakrabarty RP, Chandel NS. 2021.. Mitochondria as signaling organelles control mammalian stem cell fate. . Cell Stem Cell 28:(3):394–408
     [Crossref] [Google Scholar]
  20. Chandel NS. 2015.. Navigating Metabolism. Cold Spring Harbor, NY:: Cold Spring Harbor Lab. Press
     [Google Scholar]
  21. Chandel NS, Jasper H, Ho TT, Passegué E. 2016.. Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. . Nat. Cell Biol. 18:(8):823–32
     [Crossref] [Google Scholar]
  22. Chen S, Fan J, Xie P, Ahn J, Fernandez M, et al. 2024.. CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4. . J. Clin. Investig. 134:(8):e170071
     [Crossref] [Google Scholar]
  23. Chen X, Sunkel B, Wang M, Kang S, Wang T, et al. 2022.. Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation. . Sci. Immunol. 7:(70):eabm8161
     [Crossref] [Google Scholar]
  24. Cheung EC, Athineos D, Lee P, Ridgway RA, Lambie W, et al. 2013.. TIGAR is required for efficient intestinal regeneration and tumorigenesis. . Dev. Cell 25:(5):463–77
     [Crossref] [Google Scholar]
  25. Cheung EC, DeNicola GM, Nixon C, Blyth K, Labuschagne CF, et al. 2020.. Dynamic ROS control by TIGAR regulates the initiation and progression of pancreatic cancer. . Cancer Cell 37:(2):168–82.e4
     [Crossref] [Google Scholar]
  26. Chowdhury R, Yeoh KK, Tian Y, Hillringhaus L, Bagg EA, et al. 2011.. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. . EMBO Rep. 12:(5):463–69
     [Crossref] [Google Scholar]
  27. Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, et al. 2013.. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. . Nature 497:(7451):633–37
     [Crossref] [Google Scholar]
  28. Courtney KD, Bezwada D, Mashimo T, Pichumani K, Vemireddy V, et al. 2018.. Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo. . Cell Metab. 28:(5):793–800.e2
     [Crossref] [Google Scholar]
  29. Davidson SM, Papagiannakopoulos T, Olenchock BA, Heyman JE, Keibler MA, et al. 2016.. Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. . Cell Metab. 23:(3):517–28
     [Crossref] [Google Scholar]
  30. De Almeida MJ, Luchsinger LL, Corrigan DJ, Williams LJ, Snoeck H-W. 2017.. Dye-independent methods reveal elevated mitochondrial mass in hematopoietic stem cells. . Cell Stem Cell 21:(6):725–29.e4
     [Crossref] [Google Scholar]
  31. De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, et al. 2013.. Role of PFKFB3-driven glycolysis in vessel sprouting. . Cell 154:(3):651–63
     [Crossref] [Google Scholar]
  32. De Martino M, Rathmell JC, Galluzzi L, Vanpouille-Box C. 2024.. Cancer cell metabolism and antitumour immunity. . Nat. Rev. Immunol. https://doi.org/10.1038/s41577-024-01026-4. Erratum . 2024.. Nat. Rev. Immunol. 24::537
     [Crossref] [Google Scholar]
  33. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, et al. 2011.. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. . Nature 475:(7354):106–9
     [Crossref] [Google Scholar]
  34. Dey P, Kimmelman AC, DePinho RA. 2021.. Metabolic codependencies in the tumor microenvironment. . Cancer Discov. 11:(5):1067–81
     [Crossref] [Google Scholar]
  35. Diebold LP, Gil HJ, Gao P, Martinez CA, Weinberg SE, Chandel NS. 2019.. Mitochondrial complex III is necessary for endothelial cell proliferation during angiogenesis. . Nat. Metab. 1:(1):158–71
     [Crossref] [Google Scholar]
  36. Drijvers JM, Gillis JE, Muijlwijk T, Nguyen TH, Gaudiano EF, et al. 2021.. Pharmacologic screening identifies metabolic vulnerabilities of CD8+ T cells. . Cancer Immunol. Res. 9:(2):184–99
     [Crossref] [Google Scholar]
  37. Eelen G, Dubois C, Cantelmo AR, Goveia J, Brüning U, et al. 2018.. Role of glutamine synthetase in angiogenesis beyond glutamine synthesis. . Nature 561:(7721):63–69
     [Crossref] [Google Scholar]
  38. Elia I, Haigis MC. 2021.. Metabolites and the tumour microenvironment: from cellular mechanisms to systemic metabolism. . Nat. Metab. 3:(1):21–32
     [Crossref] [Google Scholar]
  39. Elia I, Rowe JH, Johnson S, Joshi S, Notarangelo G, et al. 2022.. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells. . Cell Metab. 34:(8):1137–50.e6
     [Crossref] [Google Scholar]
  40. Falkenberg KD, Rohlenova K, Luo Y, Carmeliet P. 2019.. The metabolic engine of endothelial cells. . Nat. Metab. 1:(10):937–46
     [Crossref] [Google Scholar]
  41. Farge T, Saland E, de Toni F, Aroua N, Hosseini M, et al. 2017.. Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism. . Cancer Discov. 7:(7):716–35
     [Crossref] [Google Scholar]
  42. Faubert B, Solmonson A, DeBerardinis RJ. 2020.. Metabolic reprogramming and cancer progression. . Science 368:(6487):eaaw5473
     [Crossref] [Google Scholar]
  43. Field CS, Baixauli F, Kyle RL, Puleston DJ, Cameron AM, et al. 2020.. Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for Treg suppressive function. . Cell Metab. 31:(2):422–37.e5
     [Crossref] [Google Scholar]
  44. Filippi M-D, Ghaffari S. 2019.. Mitochondria in the maintenance of hematopoietic stem cells: new perspectives and opportunities. . Blood 133:(18):1943–52
     [Crossref] [Google Scholar]
  45. Finley LWS. 2023.. What is cancer metabolism?. Cell 186:(8):1670–88
     [Crossref] [Google Scholar]
  46. Flores A, Schell J, Krall AS, Jelinek D, Miranda M, et al. 2017.. Lactate dehydrogenase activity drives hair follicle stem cell activation. . Nat. Cell Biol. 19:(9):1017–26
     [Crossref] [Google Scholar]
  47. Fu Z, Ye J, Dean JW, Bostick JW, Weinberg SE, et al. 2019.. Requirement of mitochondrial transcription factor A in tissue-resident regulatory T cell maintenance and function. . Cell Rep. 28:(1):159–71.e4
     [Crossref] [Google Scholar]
  48. Garcia-Bermudez J, Badgley MA, Prasad S, Baudrier L, Liu Y, et al. 2022.. Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia. . Nat. Metab. 4:(6):724–38
     [Crossref] [Google Scholar]
  49. Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ, et al. 2016.. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. . Nat. Immunol. 17:(12):1459–66
     [Crossref] [Google Scholar]
  50. Ghergurovich JM, Lang JD, Levin MK, Briones N, Facista SJ, et al. 2021.. Local production of lactate, ribose phosphate, and amino acids by human triple-negative breast cancer. . Med 2:(6):736–54.e6
     [Crossref] [Google Scholar]
  51. Gorelick AN, Kim M, Chatila WK, La K, Hakimi AA, et al. 2021.. Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA. . Nat. Metab. 3:(4):558–70
     [Crossref] [Google Scholar]
  52. Hämäläinen RH, Ahlqvist KJ, Ellonen P, Lepistö M, Logan A, et al. 2015.. mtDNA mutagenesis disrupts pluripotent stem cell function by altering redox signaling. . Cell Rep. 11:(10):1614–24
     [Crossref] [Google Scholar]
  53. Hamanaka RB, Glasauer A, Hoover P, Yang S, Blatt H, et al. 2013.. Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. . Sci. Signal. 6:(261):ra8
     [Crossref] [Google Scholar]
  54. Han S, Lee M, Shin Y, Giovanni R, Chakrabarty RP, et al. 2023.. Mitochondrial integrated stress response controls lung epithelial cell fate. . Nature 620:(7975):890–97
     [Crossref] [Google Scholar]
  55. Harris IS, DeNicola GM. 2020.. The complex interplay between antioxidants and ROS in cancer. . Trends Cell Biol. 30:(6):440–51
     [Crossref] [Google Scholar]
  56. Harris IS, Treloar AE, Inoue S, Sasaki M, Gorrini C, et al. 2015.. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. . Cancer Cell 27:(2):211–22
     [Crossref] [Google Scholar]
  57. Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E, et al. 2016.. Metabolic heterogeneity in human lung tumors. . Cell 164:(4):681–94
     [Crossref] [Google Scholar]
  58. Herkenne S, Ek O, Zamberlan M, Pellattiero A, Chergova M, et al. 2020.. Developmental and tumor angiogenesis requires the mitochondria-shaping protein OPA1. . Cell Metab. 31:(5):987–1003.e8
     [Crossref] [Google Scholar]
  59. Hinge A, He J, Bartram J, Javier J, Xu J, et al. 2020.. Asymmetrically segregated mitochondria provide cellular memory of hematopoietic stem cell replicative history and drive HSC attrition. . Cell Stem Cell 26:(3):420–30.e6
     [Crossref] [Google Scholar]
  60. Ho TT, Warr MR, Adelman ER, Lansinger OM, Flach J, et al. 2017.. Autophagy maintains the metabolism and function of young and old stem cells. . Nature 543:(7644):205–10
     [Crossref] [Google Scholar]
  61. Hosseini M, Dousset L, Mahfouf W, Serrano-Sanchez M, Redonnet-Vernhet I, et al. 2018.. Energy metabolism rewiring precedes UVB-induced primary skin tumor formation. . Cell Rep. 23:(12):3621–34
     [Crossref] [Google Scholar]
  62. Intlekofer AM, Dematteo RG, Venneti S, Finley LWS, Lu C, et al. 2015.. Hypoxia induces production of L-2-hydroxyglutarate. . Cell Metab. 22:(2):304–11
     [Crossref] [Google Scholar]
  63. Ishizawa J, Zarabi SF, Davis RE, Halgas O, Nii T, et al. 2019.. Mitochondrial ClpP-mediated proteolysis induces selective cancer cell lethality. . Cancer Cell 35:(5):721–37.e9
     [Crossref] [Google Scholar]
  64. Jackson BT, Finley LWS. 2024.. Metabolic regulation of the hallmarks of stem cell biology. . Cell Stem Cell 31:(2):161–80
     [Crossref] [Google Scholar]
  65. Jang Y-Y, Sharkis SJ. 2007.. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. . Blood 110:(8):3056–63
     [Crossref] [Google Scholar]
  66. Jiang X, Stockwell BR, Conrad M. 2021.. Ferroptosis: mechanisms, biology and role in disease. . Nat. Rev. Mol. Cell Biol. 22:(4):266–82
     [Crossref] [Google Scholar]
  67. Joshi S, Tolkunov D, Aviv H, Hakimi AA, Yao M, et al. 2015.. The genomic landscape of renal oncocytoma identifies a metabolic barrier to tumorigenesis. . Cell Rep. 13:(9):1895–908
     [Crossref] [Google Scholar]
  68. Jun S, Mahesula S, Mathews TP, Martin-Sandoval MS, Zhao Z, et al. 2021.. The requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage. . Cell Metab. 33:(9):1777–92.e8
     [Crossref] [Google Scholar]
  69. Juntilla MM, Patil VD, Calamito M, Joshi RP, Birnbaum MJ, Koretzky GA. 2010.. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. . Blood 115:(20):4030–38
     [Crossref] [Google Scholar]
  70. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. 2005.. Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. . Cell 120:(5):649–61
     [Crossref] [Google Scholar]
  71. Khacho M, Clark A, Svoboda DS, Azzi J, MacLaurin JG, et al. 2016.. Mitochondrial dynamics impacts stem cell identity and fate decisions by regulating a nuclear transcriptional program. . Cell Stem Cell 19:(2):232–47
     [Crossref] [Google Scholar]
  72. Kim J, Kundu M, Viollet B, Guan K-L. 2011.. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. . Nat. Cell Biol. 13:(2):132–41
     [Crossref] [Google Scholar]
  73. Kim M, Costello J. 2017.. DNA methylation: an epigenetic mark of cellular memory. . Exp. Mol. Med. 49:(4):e322
     [Crossref] [Google Scholar]
  74. Kim M, Mahmood M, Reznik E, Gammage PA. 2022.. Mitochondrial DNA is a major source of driver mutations in cancer. . Trends Cancer 8:(12):1046–59
     [Crossref] [Google Scholar]
  75. King A, Selak MA, Gottlieb E. 2006.. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. . Oncogene 25:(34):4675–82
     [Crossref] [Google Scholar]
  76. Konaté MM, Antony S, Doroshow JH. 2020.. Inhibiting the activity of NADPH oxidase in cancer. . Antioxid. Redox Signal. 33:(6):435–54
     [Crossref] [Google Scholar]
  77. Kong H, Reczek CR, McElroy GS, Steinert EM, Wang T, et al. 2020.. Metabolic determinants of cellular fitness dependent on mitochondrial reactive oxygen species. . Sci. Adv. 6:(45):eabb7272
     [Crossref] [Google Scholar]
  78. Kurniawan H, Franchina DG, Guerra L, Bonetti L, Soriano-Baguet L, et al. 2020.. Glutathione restricts serine metabolism to preserve regulatory T cell function. . Cell Metab. 31:(5):920–36.e7
     [Crossref] [Google Scholar]
  79. Le Gal K, Ibrahim MX, Wiel C, Sayin VI, Akula MK, et al. 2015.. Antioxidants can increase melanoma metastasis in mice. . Sci. Transl. Med. 7:(308):308re8
     [Crossref] [Google Scholar]
  80. Liang R, Arif T, Kalmykova S, Kasianov A, Lin M, et al. 2020.. Restraining lysosomal activity preserves hematopoietic stem cell quiescence and potency. . Cell Stem Cell 26:(3):359–76.e7
     [Crossref] [Google Scholar]
  81. Lignitto L, LeBoeuf SE, Homer H, Jiang S, Askenazi M, et al. 2019.. Nrf2 activation promotes lung cancer metastasis by inhibiting the degradation of Bach1. . Cell 178:(2):316–29.e18
     [Crossref] [Google Scholar]
  82. Ly CH, Lynch GS, Ryall JG. 2020.. A metabolic roadmap for somatic stem cell fate. . Cell Metab. 31:(6):1052–67
     [Crossref] [Google Scholar]
  83. Ma EH, Verway MJ, Johnson RM, Roy DG, Steadman M, et al. 2019.. Metabolic profiling using stable isotope tracing reveals distinct patterns of glucose utilization by physiologically activated CD8+ T cells. . Immunity 51:(5):856–70.e5
     [Crossref] [Google Scholar]
  84. Ma W, Gil HJ, Liu X, Diebold LP, Morgan MA, et al. 2021.. Mitochondrial respiration controls the Prox1-Vegfr3 feedback loop during lymphatic endothelial cell fate specification and maintenance. . Sci. Adv. 7:(18):eabe7359
     [Crossref] [Google Scholar]
  85. Marchi S, Guilbaud E, Tait SWG, Yamazaki T, Galluzzi L. 2023.. Mitochondrial control of inflammation. . Nat. Rev. Immunol. 23:(3):159–73
     [Crossref] [Google Scholar]
  86. Martínez-Reyes I, Cardona LR, Kong H, Vasan K, McElroy GS, et al. 2020.. Mitochondrial ubiquinol oxidation is necessary for tumour growth. . Nature 585:(7824):288–92
     [Crossref] [Google Scholar]
  87. Martínez-Reyes I, Chandel NS. 2020.. Mitochondrial TCA cycle metabolites control physiology and disease. . Nat. Commun. 11:(1):102
     [Crossref] [Google Scholar]
  88. Maryanovich M, Zaltsman Y, Ruggiero A, Goldman A, Shachnai L, et al. 2015.. An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate. . Nat. Commun. 6:(1):7901
     [Crossref] [Google Scholar]
  89. Matsushita M, Freigang S, Schneider C, Conrad M, Bornkamm GW, Kopf M. 2015.. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. . J. Exp. Med. 212:(4):555–68
     [Crossref] [Google Scholar]
  90. Mayers JR, Torrence ME, Danai LV, Papagiannakopoulos T, Davidson SM, et al. 2016.. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. . Science 353:(6304):1161–65
     [Crossref] [Google Scholar]
  91. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, et al. 2011.. Cutting edge: Distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. . J. Immunol. 186:(6):3299–303
     [Crossref] [Google Scholar]
  92. Miranda M, Christofk H, Jones DL, Lowry WE. 2018.. Topical inhibition of the electron transport chain can stimulate the hair cycle. . J. Investig. Dermatol. 138:(4):968–72
     [Crossref] [Google Scholar]
  93. Mohyeldin A, Garzón-Muvdi T, Quiñones-Hinojosa A. 2010.. Oxygen in stem cell biology: a critical component of the stem cell niche. . Cell Stem Cell 7:(2):150–61
     [Crossref] [Google Scholar]
  94. Nanadikar MS, Vergel Leon AM, Guo J, van Belle GJ, Jatho A, et al. 2023.. IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart. . Nat. Commun. 14:(1):2123
     [Crossref] [Google Scholar]
  95. Norddahl GL, Pronk CJ, Wahlestedt M, Sten G, Nygren JM, et al. 2011.. Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. . Cell Stem Cell 8:(5):499–510
     [Crossref] [Google Scholar]
  96. Oldham WM, Clish CB, Yang Y, Loscalzo J. 2015.. Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. . Cell Metab. 22:(2):291–303
     [Crossref] [Google Scholar]
  97. Pachnis P, Wu Z, Faubert B, Tasdogan A, Gu W, et al. 2022.. In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors. . Sci. Adv. 8:(35):eabn9550
     [Crossref] [Google Scholar]
  98. Paul MK, Bisht B, Darmawan DO, Chiou R, Ha VL, et al. 2014.. Dynamic changes in intracellular ROS levels regulate airway basal stem cell homeostasis through Nrf2-dependent notch signaling. . Cell Stem Cell 15:(2):199–214
     [Crossref] [Google Scholar]
  99. Petrelli F, Scandella V, Montessuit S, Zamboni N, Martinou J-C, Knobloch M. 2023.. Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells. . Sci. Adv. 9:(9):eadd5220
     [Crossref] [Google Scholar]
  100. Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, et al. 2015.. Oxidative stress inhibits distant metastasis by human melanoma cells. . Nature 527:(7577):186–91
     [Crossref] [Google Scholar]
  101. Poillet-Perez L, Xie X, Zhan L, Yang Y, Sharp DW, et al. 2018.. Autophagy maintains tumour growth through circulating arginine. . Nature 563:(7732):569–73
     [Crossref] [Google Scholar]
  102. Post Y, Clevers H. 2019.. Defining adult stem cell function at its simplest: the ability to replace lost cells through mitosis. . Cell Stem Cell 25:(2):174–83
     [Crossref] [Google Scholar]
  103. Ramirez C, Hauser AD, Vucic EA, Bar-Sagi D. 2019.. Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis. . Nature 576:(7787):477–81
     [Crossref] [Google Scholar]
  104. Raud B, Roy DG, Divakaruni AS, Tarasenko TN, Franke R, et al. 2018.. Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. . Cell Metab. 28:(3):504–15.e7
     [Crossref] [Google Scholar]
  105. Rodriguez-Berriguete G, Puliyadi R, Machado N, Barberis A, Prevo R, et al. 2024.. Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models. . Cell Death Dis. 15:(1):32
     [Crossref] [Google Scholar]
  106. Ron-Harel N, Santos D, Ghergurovich JM, Sage PT, Reddy A, et al. 2016.. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. . Cell Metab. 24:(1):104–17
     [Crossref] [Google Scholar]
  107. Savage PA, Klawon DEJ, Miller CH. 2020.. Regulatory T cell development. . Annu. Rev. Immunol. 38::421–53
     [Crossref] [Google Scholar]
  108. Sayin VI, LeBoeuf SE, Papagiannakopoulos T. 2019.. Targeting metabolic bottlenecks in lung cancer. . Trends Cancer 5:(8):457–59
     [Crossref] [Google Scholar]
  109. Schell JC, Wisidagama DR, Bensard C, Zhao H, Wei P, et al. 2017.. Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. . Nat. Cell Biol. 19:(9):1027–36
     [Crossref] [Google Scholar]
  110. Schiffmann LM, Werthenbach JP, Heintges-Kleinhofer F, Seeger JM, Fritsch M, et al. 2020.. Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth. . Nat. Commun. 11:(1):3653
     [Crossref] [Google Scholar]
  111. Schoors S, Bruning U, Missiaen R, Queiroz KCS, Borgers G, et al. 2015.. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. . Nature 520:(7546):192–97
     [Crossref] [Google Scholar]
  112. Schvartzman JM, Thompson CB, Finley LWS. 2018.. Metabolic regulation of chromatin modifications and gene expression. . J. Cell Biol. 217:(7):2247–59
     [Crossref] [Google Scholar]
  113. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, et al. 2013.. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. . Immunity 38:(2):225–36
     [Crossref] [Google Scholar]
  114. Shen K, Pender CL, Bar-Ziv R, Zhang H, Wickham K, et al. 2022.. Mitochondria as cellular and organismal signaling hubs. . Annu. Rev. Cell Dev. Biol. 38::179–218
     [Crossref] [Google Scholar]
  115. Sies H, Jones DP. 2020.. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. . Nat. Rev. Mol. Cell Biol. 21:(7):363–83
     [Crossref] [Google Scholar]
  116. Skwarski M, McGowan DR, Belcher E, Di Chiara F, Stavroulias D, et al. 2021.. Mitochondrial inhibitor atovaquone increases tumor oxygenation and inhibits hypoxic gene expression in patients with non-small cell lung cancer. . Clin. Cancer Res. 27:(9):2459–69
     [Crossref] [Google Scholar]
  117. Steinert EM, Vasan K, Chandel NS. 2021.. Mitochondrial metabolism regulation of T cell-mediated immunity. . Annu. Rev. Immunol. 39::395–416
     [Crossref] [Google Scholar]
  118. Sukumar M, Kishton RJ, Restifo NP. 2017.. Metabolic reprograming of anti-tumor immunity. . Curr. Opin. Immunol. 46::14–22
     [Crossref] [Google Scholar]
  119. Sukumar M, Liu J, Mehta GU, Patel SJ, Roychoudhuri R, et al. 2016.. Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. . Cell Metab. 23:(1):63–76
     [Crossref] [Google Scholar]
  120. Takubo K, Nagamatsu G, Kobayashi CI, Nakamura-Ishizu A, Kobayashi H, et al. 2013.. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. . Cell Stem Cell 12:(1):49–61
     [Crossref] [Google Scholar]
  121. Tan H, Yang K, Li Y, Shaw TI, Wang Y, et al. 2017.. Integrative proteomics and phosphoproteomics profiling reveals dynamic signaling networks and bioenergetics pathways underlying T cell activation. . Immunity 46:(3):488–503
     [Crossref] [Google Scholar]
  122. Tarasenko TN, Pacheco SE, Koenig MK, Gomez-Rodriguez J, Kapnick SM, et al. 2017.. Cytochrome c oxidase activity is a metabolic checkpoint that regulates cell fate decisions during T cell activation and differentiation. . Cell Metab. 25:(6):1254–68.e7
     [Crossref] [Google Scholar]
  123. Tasdogan A, Faubert B, Ramesh V, Ubellacker JM, Shen B, et al. 2020.. Metabolic heterogeneity confers differences in melanoma metastatic potential. . Nature 577:(7788):115–20
     [Crossref] [Google Scholar]
  124. Tonks NK. 2006.. Protein tyrosine phosphatases: from genes, to function, to disease. . Nat. Rev. Mol. Cell Biol. 7:(11):833–46
     [Crossref] [Google Scholar]
  125. Tormos KV, Anso E, Hamanaka RB, Eisenbart J, Joseph J, et al. 2011.. Mitochondrial complex III ROS regulate adipocyte differentiation. . Cell Metab. 14:(4):537–44
     [Crossref] [Google Scholar]
  126. Tran DH, Kim D, Kesavan R, Brown H, Dey T, et al. 2024.. De novo and salvage purine synthesis pathways across tissues and tumors. . Cell 187:(14):3602–18.e20
     [Crossref] [Google Scholar]
  127. Tran TQ, Hanse EA, Habowski AN, Li H, Ishak Gabra MB, et al. 2020.. α-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer. . Nat. Cancer 1:(3):345–58
     [Crossref] [Google Scholar]
  128. Trentesaux C, Fraudeau M, Pitasi CL, Lemarchand J, Jacques S, et al. 2020.. Essential role for autophagy protein ATG7 in the maintenance of intestinal stem cell integrity. . PNAS 117:(20):11136–46
     [Crossref] [Google Scholar]
  129. Tsutsumi R, Harizanova J, Stockert R, Schröder K, Bastiaens PIH, Neel BG. 2017.. Assay to visualize specific protein oxidation reveals spatio-temporal regulation of SHP2. . Nat. Commun. 8:(1):466
     [Crossref] [Google Scholar]
  130. Ubellacker JM, Tasdogan A, Ramesh V, Shen B, Mitchell EC, et al. 2020.. Lymph protects metastasizing melanoma cells from ferroptosis. . Nature 585:(7823):113–18
     [Crossref] [Google Scholar]
  131. Valcarcel-Jimenez L, Frezza C. 2023.. Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism. . Br. J. Cancer 129:(10):1546–57
     [Crossref] [Google Scholar]
  132. Van Soest DMK, Polderman PE, Den Toom WTF, Keijer JP, Van Roosmalen MJ, et al. 2024.. Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA. . Nat. Commun. 15:(1):2725
     [Crossref] [Google Scholar]
  133. Vasan K, Chandel NS. 2024.. Molecular and cellular mechanisms underlying the failure of mitochondrial metabolism drugs in cancer clinical trials. . J. Clin. Investig. 134:(3):e176736
     [Crossref] [Google Scholar]
  134. Venneti S, Kawakibi AR, Ji S, Waszak SM, Sweha SR, . 2023.. Clinical efficacy of ONC201 in H3K27M-mutant diffuse midline gliomas is driven by disruption of integrated metabolic and epigenetic pathways. . Cancer Discov. 13:(11):237093
     [Crossref] [Google Scholar]
  135. Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sánchez N, et al. 2014.. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. . Nature 514:(7524):628–32
     [Crossref] [Google Scholar]
  136. Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, et al. 2010.. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. . PNAS 107:(19):8788–93
     [Crossref] [Google Scholar]
  137. Weinberg SE, Singer BD, Steinert EM, Martinez CA, Mehta MM, et al. 2019.. Mitochondrial complex III is essential for suppressive function of regulatory T cells. . Nature 565:(7740):495–99
     [Crossref] [Google Scholar]
  138. Weng X, Kumar A, Cao L, He Y, Morgun E, et al. 2021.. Mitochondrial metabolism is essential for invariant natural killer T cell development and function. . PNAS 118:(13):e2021385118
     [Crossref] [Google Scholar]
  139. Wilde BR, Chakraborty N, Matulionis N, Hernandez S, Ueno D, et al. 2023.. FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer. . Cancer Discov. 13:(9):2072–89
     [Crossref] [Google Scholar]
  140. Woo DK, Green PD, Santos JH, D'Souza AD, Walther Z, et al. 2012.. Mitochondrial genome instability and ROS enhance intestinal tumorigenesis in APC mice. . Am. J. Pathol. 180:(1):24–31
     [Crossref] [Google Scholar]
  141. Wu H, Zhao X, Hochrein SM, Eckstein M, Gubert GF, et al. 2023.. Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming. . Nat. Commun. 14:(1):6858
     [Crossref] [Google Scholar]
  142. Wu K, El Zowalaty AE, Sayin VI, Papagiannakopoulos T. 2024.. The pleiotropic functions of reactive oxygen species in cancer. . Nat. Cancer 5:(3):384–99
     [Crossref] [Google Scholar]
  143. Wu Z, Bezwada D, Cai F, Harris RC, Ko B, et al. 2024.. Electron transport chain inhibition increases cellular dependence on purine transport and salvage. . Cell Metab. 36:(7):1504–20.e9
     [Crossref] [Google Scholar]
  144. Xiong Q, Jiang K, Shen X, Ma Z, Yan X, et al. 2024.. The requirement of the mitochondrial protein NDUFS8 for angiogenesis. . Cell Death Dis. 15:(4):253
     [Crossref] [Google Scholar]
  145. Xu W, Yang H, Liu Y, Yang Y, Wang P, et al. 2011.. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. . Cancer Cell 19:(1):17–30
     [Crossref] [Google Scholar]
  146. Yuan Y, Ju YS, Kim Y, Li J, Wang Y, et al. 2020.. Comprehensive molecular characterization of mitochondrial genomes in human cancers. . Nat. Genet. 52:(3):342–52
     [Crossref] [Google Scholar]
  147. Yuneva MO, Fan TWM, Allen TD, Higashi RM, Ferraris DV, et al. 2012.. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. . Cell Metab. 15:(2):157–70
     [Crossref] [Google Scholar]
  148. Zhu XG, Chudnovskiy A, Baudrier L, Prizer B, Liu Y, et al. 2021.. Functional genomics in vivo reveal metabolic dependencies of pancreatic cancer cells. . Cell Metab. 33:(1):211–21.e6
     [Crossref] [Google Scholar]
  149. Zimmermann FA, Mayr JA, Neureiter D, Feichtinger R, Alinger B, et al. 2009.. Lack of complex I is associated with oncocytic thyroid tumours. . Br. J. Cancer 100:(9):1434–37
     [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-061424-125611
Loading
Distinct Essentiality of the Mitochondrial Respiratory Chain in Proliferating Cells In Vivo
Annual Review of Cancer Biology 9, 59 (2025); https://doi.org/10.1146/annurev-cancerbio-061424-125611
/content/journals/10.1146/annurev-cancerbio-061424-125611
/content/journals/10.1146/annurev-cancerbio-061424-125611
Loading

Data & Media loading...

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error