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Decoding the mitochondria without a code: mechanistic insights into mitochondrial DNA depletion syndromes

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Abstract

Mitochondrial DNA depletion syndromes (MDS) encompass a wide spectrum of rare genetic disorders caused by severe reduction in mitochondrial DNA (mtDNA), and exhibit heterogenous phenotypes classified as myopathic, encephalomyopathic, hepatocerebral, and neurogastrointestinal. Prognosis for such a spectrum of diseases is poor and is majorly dependent on symptomatic treatment and nutritional supplementation. Understanding the mechanistic aspect of mtDNA depletion can help bring forth a new era of medicine, moving beyond symptomatic treatment and focusing more on organelle-targeted therapies. In this review, we highlight some of the proposed mechanistic bases of mtDNA depletion and the latest therapeutic measures used to treat MDS.

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Acknowledgements

We are grateful to the members of the Autophagy Laboratory (JNCASR), Rahul Dubey, and Aparna Hebbar for their valuable inputs and critical review of the manuscript. We thank all the researchers who have contributed to the field of mitochondrial DNA depletion syndromes and sincerely apologize to researchers whose work could not be acknowledged due to space constraints. The figures were created with BioRender.com under a paid subscription.

Funding

This work is supported by the S. Ramachandran-National Bioscience Award for Career Development (NBACD)-2020-21 (SAN No.102/ IFD/SAN/990/2021-22) and JNCASR intramural funds to RM, DBT-JRF programme to CJ, and JNCASR scholarship to RS.

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  1. Autophagy Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India

    Ritoprova Sen, Cuckoo Teresa Jetto & Ravi Manjithaya

  2. Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India

    Ravi Manjithaya

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RS contributed to the following sections: ‘Mechanistic overview of mitochondrial DNA copy number maintenance under homeostatic conditions’, ‘Mitochondrial DNA depletion syndromes: A mechanistic perspective’, figure 1, figure 2, figure 3 and figure 4. CJ contributed to ‘Therapeutic interventions for the treatment of mitochondrial DNA depletion syndromes’, and table 1. RM contributed to the conceptualization and critical review of the manuscript.

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Correspondence to Ravi Manjithaya.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Corresponding editor: Rakesh K Mishra

This article is part of the Topical Collection: The Rare Genetic Disease Research Landscape in India.

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Sen, R., Jetto, C.T. & Manjithaya, R. Decoding the mitochondria without a code: mechanistic insights into mitochondrial DNA depletion syndromes. J Biosci 49, 32 (2024). https://doi.org/10.1007/s12038-024-00428-9

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