Abstract
As mitochondria have crucial roles in metabolism and signaling, their structure and function must be continuously monitored and rapidly adjusted to meet cellular demands. Critical to this regulation is a conserved stress response that detects and alleviates challenges to mitochondrial integrity. Recent work has shown that mitochondrial stress often elicits simultaneous protective reactions that act in a coordinated and tightly regulated fashion to preserve this essential organelle. Here we review components, coordination and control within this comprehensive stress response and discuss how increased understanding of mitochondrial stress signaling is beginning to inform therapeutic approaches directed against diseases of high unmet need.
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Acknowledgements
We thank all members of our lab for continuous discussions and support and for building a collaborative environment that is characterized by extensive crosstalk and coordination. M.R. is an investigator of the Howard Hughes Medical Institute. This work was also supported by a National Institute of General Medical Sciences R01 grant to MR (GM151335-01). J.B.S. is a Howard Hughes Medical Institute fellow of the Damon Runyon Cancer Research Foundation (DRG-2487-23).
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M.R. is a cofounder and scientific advisory board member of Nurix Therapeutics; cofounder, consultant and scientific advisory board member of Lyterian Therapeutics; cofounder and consultant of Zenith Therapeutics; cofounder of Reina Therapeutics; and iPartner at The Column Group. The other authors declare no competing interests.
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Sheetz, J.B., Chandrasekhar, S. & Rapé, M. Function and regulation of the mitochondrial stress response. Nat Struct Mol Biol 33, 382–393 (2026). https://doi.org/10.1038/s41594-026-01769-9
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DOI: https://doi.org/10.1038/s41594-026-01769-9
