Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mitochondrial heterogeneity and adaptations to cellular needs

Nature Cell Biology volume 26, pages 674–686 (2024)Cite this article

Subjects

Abstract

Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Changes in mitochondrial metabolism that drive progenitor cell behaviours.
Fig. 2: Adipocyte plasticity in tissue remodelling.
Fig. 3: Exercise-adapted versus sedentary mitochondria.
Fig. 4: Mitochondrial fuel source selection in the fed versus fasted state.

Similar content being viewed by others

References

  1. Spinelli, J. B. & Haigis, M. C. The multifaceted contributions of mitochondria to cellular metabolism. Nat. Cell Biol. 20, 745–754 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bahat, A. & Gross, A. Mitochondrial plasticity in cell fate regulation. J. Biol. Chem. 294, 13852–13863 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mehta, M. M., Weinberg, S. E. & Chandel, N. S. Mitochondrial control of immunity: beyond ATP. Nat. Rev. Immunol. 17, 608–620 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Fecher, C. et al. Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity. Nat. Neurosci. 22, 1731–1742 (2019).

    Article  CAS  PubMed  Google Scholar 

  5. Kajimura, S. & Saito, M. A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis. Annu. Rev. Physiol. 76, 225–249 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Yook, J.-S. et al. The SLC25A47 locus controls gluconeogenesis and energy expenditure. Proc. Natl Acad. Sci. USA 120, e2216810120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lesner, N. P. et al. Differential requirements for mitochondrial electron transport chain components in the adult murine liver. eLife 11, e80919 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Diaz-Cuadros, M. et al. Metabolic regulation of species-specific developmental rates. Nature 613, 550–557 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Burr, S. P. et al. Cell lineage-specific mitochondrial resilience during mammalian organogenesis. Cell 186, 1212–1229 (2023).

    Article  CAS  PubMed  Google Scholar 

  10. Huppertz, I. et al. Riboregulation of enolase 1 activity controls glycolysis and embryonic stem cell differentiation. Mol. Cell 82, 2666–2680 (2022).

    Article  CAS  PubMed  Google Scholar 

  11. Gu, W. et al. Glycolytic metabolism plays a functional role in regulating human pluripotent stem cell state. Cell Stem Cell 19, 476–490 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Xu, X. et al. Mitochondrial regulation in pluripotent stem cells. Cell Metab. 18, 325–332 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Intlekofer, A. M. & Finley, L. W. S. Metabolic signatures of cancer cells and stem cells. Nat. Metab. 1, 177–188 (2019).

  14. Hicks, M. R. & Pyle, A. D. The emergence of the stem cell niche. Trends Cell Biol. 33, 112–123 (2023).

    Article  PubMed  Google Scholar 

  15. Mohyeldin, A., Garzón-Muvdi, T. & Quiñones-Hinojosa, A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 7, 150–161 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. De Almeida, M. J., Luchsinger, L. L., Corrigan, D. J., Williams, L. J. & Snoeck, H.-W. Dye-independent methods reveal elevated mitochondrial mass in hematopoietic stem cells. Cell Stem Cell 21, 725–729 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ansó, E. et al. The mitochondrial respiratory chain is essential for haematopoietic stem cell function. Nat. Cell Biol. 19, 614–625 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Chakrabarty, R. P. & Chandel, N. S. Mitochondria as signaling organelles control mammalian stem cell fate. Cell Stem Cell 28, 394–408 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang, H. et al. Distinct metabolic states can support self-renewal and lipogenesis in human pluripotent stem cells under different culture conditions. Cell Rep. 16, 1536–1547 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhu, Q., An, Y. A. & Scherer, P. E. Mitochondrial regulation and white adipose tissue homeostasis. Trends Cell Biol. 32, 351–364 (2022).

    Article  CAS  PubMed  Google Scholar 

  21. Kladnická, I. et al. Mitochondrial respiration of adipocytes differentiating from human mesenchymal stem cells derived from adipose tissue. Physiol. Res. 68, S287–S296 (2019).

    Article  PubMed  Google Scholar 

  22. Oguri, Y. et al. CD81 controls beige fat progenitor cell growth and energy balance via FAK signaling. Cell 182, 563–577 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Joffin, N. et al. Mitochondrial metabolism is a key regulator of the fibro-inflammatory and adipogenic stromal subpopulations in white adipose tissue. Cell Stem Cell 28, 702–717 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kusminski, C. M. et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat. Med. 18, 1539–1549 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rodríguez-Colman, M. J. et al. Interplay between metabolic identities in the intestinal crypt supports stem cell function. Nature 543, 424–427 (2017).

    Article  PubMed  Google Scholar 

  26. Ludikhuize, M. C. et al. Mitochondria define intestinal stem cell differentiation downstream of a FOXO/Notch axis. Cell Metab. 32, 889–900 (2020).

    Article  CAS  PubMed  Google Scholar 

  27. Schell, J. C. et al. Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nat. Cell Biol. 19, 1027–1036 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nakamura-Ishizu, A., Ito, K. & Suda, T. Hematopoietic stem cell metabolism during development and aging. Dev. Cell 54, 239–255 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vannini, N. et al. Specification of haematopoietic stem cell fate via modulation of mitochondrial activity. Nat. Commun. 7, 13125 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lin, C. et al. Impaired mitochondrial oxidative metabolism in skeletal progenitor cells leads to musculoskeletal disintegration. Nat. Commun. 13, 6869 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wanet, A., Arnould, T., Najimi, M. & Renard, P. Connecting mitochondria, metabolism, and stem cell fate. Stem. Cells Dev. 24, 1957–1971 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Picard, M. & Shirihai, O. S. Mitochondrial signal transduction. Cell Metab. 34, 1620–1653 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Arnold, P. K. et al. A non-canonical tricarboxylic acid cycle underlies cellular identity. Nature 603, 477–481 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Scandella, V., Petrelli, F., Moore, D. L., Braun, S. M. G. & Knobloch, M. Neural stem cell metabolism revisited: a critical role for mitochondria. Trends Endocrinol. Metab. 34, 446–461 (2023).

    Article  CAS  PubMed  Google Scholar 

  35. Knobloch, M. et al. A fatty acid oxidation-dependent metabolic shift regulates adult neural stem cell activity. Cell Rep. 20, 2144–2155 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang, K. et al. Acquisition of cellular properties during alveolar formation requires differential activity and distribution of mitochondria. eLife 11, e68598 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Rangaraju, V. et al. Pleiotropic mitochondria: the influence of mitochondria on neuronal development and disease. J. Neurosci. 39, 8200–8208 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhao, J., Sun, Q., Zhou, L., Liu, K. & Jiao, K. Complex Regulation of Mitochondrial Function During Cardiac Development. J. Am. Heart Assoc. 8, e012731 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cheong, A. et al. Nuclear encoded mitochondrial ribosomal proteins are required to initiate gastrulation. Development 147, dev188714 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rodríguez-Nuevo, A. et al. Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I. Nature 607, 756–761 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kirillova, A., Smitz, J. E. J., Sukhikh, G. T. & Mazunin, I. The role of mitochondria in oocyte maturation. Cells 10, 2484 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang, L. et al. Oxidative stress in oocyte aging and female reproduction. J. Cell. Physiol. 236, 7966–7983 (2021).

    Article  CAS  PubMed  Google Scholar 

  43. Folmes, C. D. L., Dzeja, P. P., Nelson, T. J. & Terzic, A. Metabolic plasticity in stem cell homeostasis and differentiation. Cell Stem Cell 11, 596–606 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Glancy, B., Kim, Y., Katti, P. & Willingham, T. B. The functional impact of mitochondrial structure across subcellular scales. Front. Physiol. 11, 541040 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Iwata, R. et al. Mitochondria metabolism sets the species-specific tempo of neuronal development. Science 379, eabn4705 (2023).

    Article  CAS  PubMed  Google Scholar 

  46. Steiner, P. Brain fuel utilization in the developing brain. Ann. Nutr. Metab. 75, 8–18 (2019).

    Article  CAS  PubMed  Google Scholar 

  47. Nagaraj, R. et al. Nuclear localization of mitochondrial TCA cycle enzymes as a critical step in mammalian zygotic genome activation. Cell 168, 210–223 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zwick, R. K., Guerrero-Juarez, C. F., Horsley, V. & Plikus, M. V. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metab. 27, 68–83 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Auger, C. & Kajimura, S. Adipose tissue remodeling in pathophysiology. Annu. Rev. Pathol. 18, 71–93 (2023).

    Article  CAS  PubMed  Google Scholar 

  50. Abe, I. et al. Lipolysis-derived linoleic acid drives beige fat progenitor cell proliferation. Dev. Cell 57, 2623–2637 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Giordano, A., Frontini, A. & Cinti, S. Convertible visceral fat as a therapeutic target to curb obesity. Nat. Rev. Drug Discov. 15, 405–424 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Bean, C. et al. The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites. Nat. Metab. 3, 1633–1647 (2021).

    Article  CAS  PubMed  Google Scholar 

  53. Lu, X. et al. Mitophagy controls beige adipocyte maintenance through a Parkin-dependent and UCP1-independent mechanism. Sci. Signal. 11, eaap8526 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Altshuler-Keylin, S. et al. Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance. Cell Metab. 24, 402–419 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ghaben, A. L. & Scherer, P. E. Adipogenesis and metabolic health. Nat. Rev. Mol. Cell Biol. 20, 242–258 (2019).

    Article  CAS  PubMed  Google Scholar 

  56. Sun, K., Tordjman, J., Clément, K. & Scherer, P. E. Fibrosis and adipose tissue dysfunction. Cell Metab. 18, 470–477 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chouchani, E. T. & Kajimura, S. Metabolic adaptation and maladaptation in adipose tissue. Nat. Metab. 1, 189–200 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Lee, Y. S. et al. Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity. Cell 157, 1339–1352 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Seo, J. B. et al. Knockdown of ANT2 reduces adipocyte hypoxia and improves insulin resistance in obesity. Nat. Metab. 1, 86–97 (2019).

    Article  CAS  PubMed  Google Scholar 

  60. Maqdasy, S. et al. Impaired phosphocreatine metabolism in white adipocytes promotes inflammation. Nat. Metab. 4, 190–202 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rahbani, J. F. et al. Creatine kinase B controls futile creatine cycling in thermogenic fat. Nature 590, 480–485 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Serbulea, V. et al. Macrophage phenotype and bioenergetics are controlled by oxidized phospholipids identified in lean and obese adipose tissue. Proc. Natl Acad. Sci. USA 115, E6254–E6263 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Xu, L. et al. Macrophage polarization mediated by mitochondrial dysfunction induces adipose tissue inflammation in obesity. Int. J. Mol. Sci. 23, 9252 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang, Y. et al. Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages. Nat. Commun. 12, 102 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Anvari, G. & Bellas, E. Hypoxia induces stress fiber formation in adipocytes in the early stage of obesity. Sci. Rep. 11, 21473 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Fung, T. S., Chakrabarti, R. & Higgs, H. N. The multiple links between actin and mitochondria. Nat. Rev. Mol. Cell Biol. 24, 651–667 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Li, S. et al. Transient assembly of F-actin on the outer mitochondrial membrane contributes to mitochondrial fission. J. Cell Biol. 208, 109–123 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Horn, A. et al. Mitochondrial redox signaling enables repair of injured skeletal muscle cells. Sci. Signal. 10, eaaj1978 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Sitar, T. et al. Molecular architecture of the spire–actin nucleus and its implication for actin filament assembly. Proc. Natl Acad. Sci. USA 108, 19575–19580 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Manor, U. et al. A mitochondria-anchored isoform of the actin-nucleating spire protein regulates mitochondrial division. eLife 4, e08828 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Pernas, L. & Scorrano, L. Mito-morphosis: mitochondrial fusion, fission, and cristae remodeling as key mediators of cellular function. Annu. Rev. Physiol. 78, 505–531 (2016).

    Article  CAS  PubMed  Google Scholar 

  72. Guidotti, S. et al. Glycogen synthase kinase-3β inhibition links mitochondrial dysfunction, extracellular matrix remodelling and terminal differentiation in chondrocytes. Sci. Rep. 7, 12059 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bubb, K. et al. Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage. J. Biol. Chem. 297, 101224 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Tharp, K. M. et al. Adhesion-mediated mechanosignaling forces mitohormesis. Cell Metab. 33, 1322–1341 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Park, J. S. et al. Mechanical regulation of glycolysis via cytoskeleton architecture. Nature 578, 621–626 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. McLaughlin, K. L. et al. Novel approach to quantify mitochondrial content and intrinsic bioenergetic efficiency across organs. Sci. Rep. 10, 17599 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Magistretti, P. J. & Allaman, I. A cellular perspective on brain energy metabolism and functional imaging. Neuron 86, 883–901 (2015).

    Article  CAS  PubMed  Google Scholar 

  78. Ioannou, M. S. et al. Neuron-astrocyte metabolic coupling protects against activity-induced fatty acid toxicity. Cell 177, 1522–1535 (2019).

    Article  CAS  PubMed  Google Scholar 

  79. Bélanger, M., Allaman, I. & Magistretti, P. J. Brain energy metabolism: focus on astrocyte–neuron metabolic cooperation. Cell Metab. 14, 724–738 (2011).

    Article  PubMed  Google Scholar 

  80. Pekkurnaz, G. & Wang, X. Mitochondrial heterogeneity and homeostasis through the lens of a neuron. Nat. Metab. 4, 802–812 (2022).

    Article  PubMed  Google Scholar 

  81. Graham, L. C. et al. Proteomic profiling of neuronal mitochondria reveals modulators of synaptic architecture. Mol. Neurodegener. 12, 77 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Díaz-García, C. M. et al. Neuronal stimulation triggers neuronal glycolysis and not lactate uptake. Cell Metab. 26, 361–374 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Kuczynska, Z., Metin, E., Liput, M. & Buzanska, L. Covering the role of PGC-1α in the nervous system. Cells 11, 111 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Jensen, N. J., Wodschow, H. Z., Nilsson, M. & Rungby, J. Effects of ketone bodies on brain metabolism and function in neurodegenerative diseases. Int. J. Mol. Sci. 21, 8767 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Fritzen, A. M., Lundsgaard, A.-M. & Kiens, B. Tuning fatty acid oxidation in skeletal muscle with dietary fat and exercise. Nat. Rev. Endocrinol. 16, 683–696 (2020).

    Article  CAS  PubMed  Google Scholar 

  86. Hargreaves, M. & Spriet, L. L. Skeletal muscle energy metabolism during exercise. Nat. Metab. 2, 817–828 (2020).

    Article  CAS  PubMed  Google Scholar 

  87. Smith, J. A. B., Murach, K. A., Dyar, K. A. & Zierath, J. R. Exercise metabolism and adaptation in skeletal muscle. Nat. Rev. Mol. Cell Biol. 24, 607–632 (2023).

    Article  CAS  PubMed  Google Scholar 

  88. Deshmukh, A. S. et al. Deep muscle-proteomic analysis of freeze-dried human muscle biopsies reveals fiber type-specific adaptations to exercise training. Nat. Commun. 12, 304 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Reddy, A. et al. pH-gated succinate secretion regulates muscle remodeling in response to exercise. Cell 183, 62–75 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ouyang, Q. et al. Rab8a as a mitochondrial receptor for lipid droplets in skeletal muscle. Dev. Cell 58, 289–305 (2023).

    Article  CAS  PubMed  Google Scholar 

  91. Benador, I. Y., Veliova, M., Liesa, M. & Shirihai, O. S. Mitochondria bound to lipid droplets: where mitochondrial dynamics regulate lipid storage and utilization. Cell Metab. 29, 827–835 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Benador, I. Y. et al. Mitochondria bound to lipid droplets have unique bioenergetics, composition, and dynamics that support lipid droplet expansion. Cell Metab. 27, 869–885 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Furrer, R. et al. Molecular control of endurance training adaptation in male mouse skeletal muscle. Nat. Metab. 5, 2020–2035 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Wang, X. et al. Scinderin promotes fusion of electron transport chain dysfunctional muscle stem cells with myofibers. Nat. Aging 2, 155–169 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wicks, S. E. et al. Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism. Proc. Natl Acad. Sci. USA 112, E3300–E3309 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pereyra, A. S. et al. Skeletal muscle undergoes fiber type metabolic switch without myosin heavy chain switch in response to defective fatty acid oxidation. Mol. Metab. 59, 101456 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Koves, T. R. et al. Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles. Cell Metab. 35, 1038–1056 (2023).

    Article  CAS  PubMed  Google Scholar 

  98. Yasuda, T., Ishihara, T., Ichimura, A. & Ishihara, N. Mitochondrial dynamics define muscle fiber type by modulating cellular metabolic pathways. Cell Rep. 42, 112434 (2023).

    Article  CAS  PubMed  Google Scholar 

  99. Song, H. et al. CREG1 improves the capacity of the skeletal muscle response to exercise endurance via modulation of mitophagy. Autophagy 17, 4102–4118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mishra, P., Varuzhanyan, G., Pham, A. H. & Chan, D. C. Mitochondrial dynamics is a distinguishing feature of skeletal muscle fiber types and regulates organellar compartmentalization. Cell Metab. 22, 1033–1044 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hood, D. A., Memme, J. M., Oliveira, A. N. & Triolo, M. Maintenance of skeletal muscle mitochondria in health, exercise, and aging. Annu. Rev. Physiol. 81, 19–41 (2019).

    Article  CAS  PubMed  Google Scholar 

  102. Rasbach, K. A. et al. PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types. Proc. Natl Acad. Sci. USA 107, 21866–21871 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Auger, C., Alhasawi, A., Contavadoo, M. & Appanna, V. D. Dysfunctional mitochondrial bioenergetics and the pathogenesis of hepatic disorders. Front. Cell Dev. Biol. 3, 40 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Bórquez, J. C. et al. Mitofusin-2 induced by exercise modifies lipid droplet-mitochondria communication, promoting fatty acid oxidation in male mice with NAFLD. Metabolism 152, 155765 (2024).

    Article  PubMed  Google Scholar 

  105. Levine, D. C. et al. NADH inhibition of SIRT1 links energy state to transcription during time-restricted feeding. Nat. Metab. 3, 1621–1632 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Petersen, M. C., Vatner, D. F. & Shulman, G. I. Regulation of hepatic glucose metabolism in health and disease. Nat. Rev. Endocrinol. 13, 572–587 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Holeček, M. Roles of malate and aspartate in gluconeogenesis in various physiological and pathological states. Metabolism 145, 155614 (2023).

    Article  PubMed  Google Scholar 

  108. Bideyan, L., Nagari, R. & Tontonoz, P. Hepatic transcriptional responses to fasting and feeding. Genes Dev. 35, 635–657 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Méndez-Lucas, A. et al. PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis. J. Hepatol. 59, 105–113 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Bresciani, N. et al. The Slc25a47 locus is a novel determinant of hepatic mitochondrial function implicated in liver fibrosis. J. Hepatol. 77, 1071–1082 (2022).

    Article  CAS  PubMed  Google Scholar 

  111. Paris, J. & Henderson, N. C. Liver zonation, revisited. Hepatology 76, 1219–1230 (2022).

    Article  PubMed  Google Scholar 

  112. Ben-Moshe, S. & Itzkovitz, S. Spatial heterogeneity in the mammalian liver. Nat. Rev. Gastroenterol. Hepatol. 16, 395–410 (2019).

    Article  PubMed  Google Scholar 

  113. Brosch, M. et al. Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control. Nat. Commun. 9, 4150 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Goetzman, E. S. et al. Impaired mitochondrial medium-chain fatty acid oxidation drives periportal macrovesicular steatosis in sirtuin-5 knockout mice. Sci. Rep. 10, 18367 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ben-Moshe, S. et al. Spatial sorting enables comprehensive characterization of liver zonation. Nat. Metab. 1, 899–911 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Golozoubova, V. et al. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J. 15, 2048–2050 (2001).

    Article  CAS  PubMed  Google Scholar 

  117. Tai, J. et al. Hem25p is required for mitochondrial IPP transport in fungi. Nat. Cell Biol. 25, 1616–1624 (2023).

  118. Vandereyken, K., Sifrim, A., Thienpont, B. & Voet, T. Methods and applications for single-cell and spatial multi-omics. Nat. Rev. Genet. 24, 494–515 (2023).

    Article  CAS  PubMed  Google Scholar 

  119. Petrelli, F. et al. Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells. Sci. Adv. 9, eadd5220 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Tian, Z. & Liang, M. Renal metabolism and hypertension. Nat. Commun. 12, 963 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kappler, L. et al. Linking bioenergetic function of mitochondria to tissue-specific molecular fingerprints. Am. J. Physiol. Endocrinol. Metab. 317, E374–E387 (2019).

    Article  CAS  PubMed  Google Scholar 

  122. Prola, A. et al. Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle. Sci. Adv. 7, eabd6322 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Sustarsic, E. G. et al. Cardiolipin synthesis in brown and beige fat mitochondria is essential for systemic energy homeostasis. Cell Metab. 28, 159–174 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Cardoso, A. C. et al. Mitochondrial substrate utilization regulates cardiomyocyte cell cycle progression. Nat. Metab. 2, 167–178 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Schulze, P. C., Drosatos, K. & Goldberg, I. J. Lipid use and misuse by the heart. Circ. Res. 118, 1736–1751 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Hui, S. et al. Quantitative fluxomics of circulating metabolites. Cell Metab. 32, 676–688 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Paillard, M. et al. Tissue-specific mitochondrial decoding of cytoplasmic Ca2+ signals is controlled by the stoichiometry of MICU1/2 and MCU. Cell Rep. 18, 2291–2300 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zhou, W. et al. SENP1–Sirt3 signaling promotes α-ketoglutarate production during M2 macrophage polarization. Cell Rep. 39, 110660 (2022).

    Article  CAS  PubMed  Google Scholar 

  130. Liu, P.-S. et al. α-Ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994 (2017).

    Article  CAS  PubMed  Google Scholar 

  131. Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Petrus, P. et al. Glutamine links obesity to inflammation in human white adipose tissue. Cell Metab. 31, 375–390 (2020).

    Article  CAS  PubMed  Google Scholar 

  133. Yoneshiro, T. et al. Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever. eLife 10, e66865 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Yoneshiro, T. et al. BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. Nature 572, 614–619 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Galy, B., Conrad, M. & Muckenthaler, M. Mechanisms controlling cellular and systemic iron homeostasis. Nat. Rev. Mol. Cell Biol. 25, 133–155 (2023).

    Article  PubMed  Google Scholar 

  136. Tran, D. H. et al. Mitochondrial NADP+ is essential for proline biosynthesis during cell growth. Nat. Metab. 3, 571–585 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Rönn, T. et al. Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes. Nat. Commun. 14, 8040 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Walejko, J. M. et al. Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart. Nat. Commun. 12, 1680 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Murashige, D. et al. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Science 370, 364–368 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Flam, E. & Arany, Z. Metabolite signaling in the heart. Nat. Cardiovasc. Res. 2, 504–516 (2023).

    Article  Google Scholar 

  141. Durante, W. The emerging role of l-glutamine in cardiovascular health and disease. Nutrients 11, 2092 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Muoio, D. M. Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock. Cell 159, 1253–1262 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Maurer, J., Hoene, M. & Weigert, C. Signals from the circle: tricarboxylic acid cycle intermediates as myometabokines. Metabolites 11, 474 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Li, C. et al. Purkinje cell dopaminergic inputs to astrocytes regulate cerebellar-dependent behavior. Nat. Commun. 14, 1613 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Pickrell, A. M., Fukui, H., Wang, X., Pinto, M. & Moraes, C. T. The striatum is highly susceptible to mitochondrial oxidative phosphorylation dysfunctions. J. Neurosci. 31, 9895–9904 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Felix, J. B., Cox, A. R. & Hartig, S. M. Acetyl-CoA and metabolite fluxes regulate white adipose tissue expansion. Trends Endocrinol. Metab. 32, 320–332 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Kajimura, S., Spiegelman, B. M. & Seale, P. Brown and beige fat: physiological roles beyond heat generation. Cell Metab. 22, 546–559 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Wiley, S. E., Murphy, A. N., Ross, S. A., van der Geer, P. & Dixon, J. E. MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity. PNAS 104, 5318–5323 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Adusumilli, V. S. et al. ROS dynamics delineate functional states of hippocampal neural stem cells and link to their activity-dependent exit from quiescence. Cell Stem Cell 28, 300–314.e6 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge our funding sources: NIH (RO1 DK097441, RO1DK125283 and DK125281), Howard Hughes Medical Institute and the NIDDK (3DP1DK126160-04S1).

Author information

Authors and Affiliations

  1. Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA

    Melia Granath-Panelo & Shingo Kajimura

  2. Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Melia Granath-Panelo

Authors
  1. Melia Granath-Panelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shingo Kajimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Melia Granath-Panelo or Shingo Kajimura.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Cell Biology thanks Navdeep Chandel and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Granath-Panelo, M., Kajimura, S. Mitochondrial heterogeneity and adaptations to cellular needs. Nat Cell Biol 26, 674–686 (2024). https://doi.org/10.1038/s41556-024-01410-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41556-024-01410-1

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing