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Hypermetabolism and energetic constraints in mitochondrial disorders

Nature Metabolism volume 6, pages 192–195 (2024)Cite this article

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The prevailing notion that mitochondrial diseases arise from ATP deficiency is challenged by recent evidence that oxidative phosphorylation defects trigger maladaptive stress responses consuming excess energy. We argue that this chronic state of hypermetabolism imposes energetic constraints, thus causing mitochondrial disease pathophysiology, calling for careful translational studies from organelle to organism.

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Fig. 1: Proposed model of mitochondrial diseases pathophysiology centred on the (hyper)metabolic phenotype of clinical and pre-clinical models of mitochondrial OxPhos defects.

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Acknowledgements

Work of the authors is partly supported by NIH grants P30-DK26687 to D.G., R35HL155670 and R01HL142648 to M.P.S.O., R01MH122706, R01AG066828, R01MH119336, the Wharton Fund, and the Baszucki Brain Research Fund to M.P.

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Authors and Affiliations

  1. Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, USA

    Alexander J. Sercel, Gabriel Sturm & Martin Picard

  2. Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA

    Gabriel Sturm

  3. Department of Medicine, Columbia University Irving Medical Center, New York, USA

    Dympna Gallagher

  4. Division of General Medicine and Center of Excellence for Sleep & Circadian Research, Department of Medicine, Columbia University Irving Medical Center, New York, USA

    Marie-Pierre St-Onge

  5. The Santa Fe Institute, New Mexico, USA

    Christopher P. Kempes

  6. Department of Evolutionary Anthropology, Duke University, North Carolina, USA

    Herman Pontzer

  7. Duke Global Health Institute, Duke University, North Carolina, USA

    Herman Pontzer

  8. Department of Neurology, H. Houston Merritt Center, Columbia University Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, USA

    Michio Hirano & Martin Picard

  9. New York State Psychiatric Institute, New York, USA

    Martin Picard

  10. Robert N Butler Columbia Aging Center, Columbia University Mailman School of Public Health, New York, NY, USA

    Martin Picard

Authors
  1. Alexander J. Sercel
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  2. Gabriel Sturm
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  5. Christopher P. Kempes
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  8. Martin Picard
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Contributions

A.J.S. and M.P. conceived the model and prepared the manuscript. G.S., D.G., M.P.S.O., C.P.K., H.P. and M.H. made substantial conceptual and editorial contributions to the final article.

Corresponding author

Correspondence to Martin Picard.

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The authors declare no competing interests.

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Sercel, A.J., Sturm, G., Gallagher, D. et al. Hypermetabolism and energetic constraints in mitochondrial disorders. Nat Metab 6, 192–195 (2024). https://doi.org/10.1038/s42255-023-00968-8

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