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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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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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.
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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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DOI: https://doi.org/10.1038/s42255-023-00968-8