Abstract
Mitochondria are multifaceted organelles with crucial roles in energy generation, cellular signalling and a range of synthesis pathways. The study of mitochondrial biology is complicated by its own small genome, which is matrilineally inherited and not subject to recombination, and present in multiple, possibly different, copies. Recent methodological developments have enabled the analysis of mitochondrial DNA (mtDNA) in large-scale cohorts and highlight the far-reaching impact of mitochondrial genetic variation. Genome-editing techniques have been adapted to target mtDNA, further propelling the functional analysis of mitochondrial genes. Mitochondria are finely tuned signalling hubs, a concept that has been expanded by advances in methodologies for studying the function of mitochondrial proteins and protein complexes. Mitochondrial respiratory complexes are of dual genetic origin, requiring close coordination between mitochondrial and nuclear gene-expression systems (transcription and translation) for proper assembly and function, and recent findings highlight the importance of the mitochondria in this bidirectional signalling.
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Acknowledgements
We thank all members of J. Auwerx laboratory for helpful discussions. We apologize for the omission of many relevant studies due to space constraints. We are funded by grants from the EPFL, the European Research Council (ERC-AdG-787702), the Swiss National Science Foundation (SNSF 31003A_179435 and Sinergia CRSII5_202302) and a GRL grant of the National Research Foundation of Korea (NRF 2017K1A1A2013124). Y.J.L. was supported by a postdoctoral fellowship from the European Molecular Biology Organization (EMBO, ALTF 1161-2021).
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Liu, Y.J., Sulc, J. & Auwerx, J. Mitochondrial genetics, signalling and stress responses. Nat Cell Biol 27, 393–407 (2025). https://doi.org/10.1038/s41556-025-01625-w
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DOI: https://doi.org/10.1038/s41556-025-01625-w
