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An alternative model for maternal mtDNA inheritance

Nature Genetics volume 57, pages 1103–1104 (2025)Cite this article

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Matters Arising to this article was published on 20 March 2025

The Original Article was published on 18 September 2023

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arising from W. Lee et al. Nature Genetics https://doi.org/10.1038/s41588-023-01505-9 (2023)

The exact mechanism preventing paternal mitochondrial DNA (mtDNA) inheritance in humans remains unresolved. In their recent report, ‘Molecular basis for maternal inheritance of human mitochondrial DNA’, Lee et al. propose that this process is controlled by phosphorylation of the mitochondrial transcription factor A (TFAM) on two serine residues located in the matrix targeting sequence (MTS), which blocks this protein’s mitochondrial import, thus uncoating mtDNA and exposing it to attack and destruction by unspecified mitochondrial nuclease(s), which prevents paternal mtDNA from entering the oocyte during fertilization. We argue that the experimental evidence presented in the article is inconclusive and also supports an alternative possibility: that mtDNA turnover following the loss of expression of key mtDNA replication proteins might be responsible. Therefore, additional experimentation is needed to resolve the two competing mechanisms that align with the experimental data presented by Lee et al.

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Acknowledgements

We acknowledge the contributions and helpful discussions of W. Copeland and D. King as well as the insightful comments of anonymous reviewers. The authors were supported by grants from the Baptist Health Foundation of San Antonio (Y.B.), NIH 5P30CA054174 (Y.B.), 1R01CA283840 (Y.B.), 1R21AI171940 (Y.B.), HL66299 (M.A.), S10OD025089 (M.A.), NSF FAIN2419655 (M.A.), DoD 81XWH2110161 (M.A.) and W81XWH2110669 (M.A.).

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Authors and Affiliations

  1. Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, USA

    Mikhail Alexeyev

  2. Department of Cell Systems and Anatomy, the University of Texas Health San Antonio, San Antonio, TX, USA

    Yidong Bai

  3. Population Science and Prevention Program, Mays Cancer Center, the University of Texas Health San Antonio, San Antonio, TX, USA

    Yidong Bai

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  1. Mikhail Alexeyev
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  2. Yidong Bai
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The authors contributed equally to all aspects of this article.

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Correspondence to Mikhail Alexeyev.

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Nature Genetics thanks Liliana Milani and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Alexeyev, M., Bai, Y. An alternative model for maternal mtDNA inheritance. Nat Genet 57, 1103–1104 (2025). https://doi.org/10.1038/s41588-025-02149-7

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