Deciphering the Foundations of Mitochondrial Mutational Spectra: Replication-Driven and Damage-Induced Signatures Across Chordate Classes
Mitochondrial DNA (mtDNA) mutagenesis remains poorly understood despite its crucial role in disease, aging, and evolutionary tracing. In this study, we reconstructed a comprehensive 192-component mtDNA mutational spectrum for chordates by analyzing 118,397 synonymous mutations in the CytB gene across 1,697 species and five classes. This analysis revealed three primary forces shaping mtDNA mutagenesis: (i) symmetrical, replication-driven errors by mitochondrial polymerase (POLG), resulting in C > T and A > G mutations that are highly conserved across classes; (ii) asymmetrical, damage-driven C > T mutations on the single-stranded heavy strand with clock-like dynamics; and (iii) asymmetrical A > G mutations on the heavy strand, with dynamics suggesting sensitivity to oxidative damage. The third component, sensitive to oxidative damage, positions mtDNA mutagenesis as a promising marker for metabolic and physiological processes across various classes, species, organisms, tissues, and cells. The deconvolution of the mutational spectra into mutational signatures uncovered deficiencies in both base excision repair (BER) and mismatch repair (MMR) pathways. Further analysis of mutation hotspots, abasic sites, and mutational asymmetries underscores the critical role of single-stranded DNA damage (components ii and iii), which, uncorrected due to BER and MMR deficiencies, contributes roughly as many mutations as POLG-induced errors (component i).
Authors
- Bakhyt Matkarimov (ORCID: https://orcid.org/0000-0003-0775-7324)
- Stepan Denisov (ORCID: https://orcid.org/0000-0001-6465-3818)
- Konstantin Khrapko (ORCID: https://orcid.org/0000-0002-9250-8033)
- Philipp Kapranov (ORCID: https://orcid.org/0000-0003-2647-4856)
- Victor Shamanskiy (ORCID: https://orcid.org/0000-0001-7722-2232)
- Alina G. Mikhailova (ORCID: https://orcid.org/0000-0002-5494-3536)
- Ilya Mazunin (ORCID: https://orcid.org/0000-0002-5448-9679)
- Bogdan Efimenko (ORCID: https://orcid.org/0000-0001-7635-3329)
- Alexandr Voronka (ORCID: https://orcid.org/0000-0002-1534-1962)
- Dmitrii Iliushchenko (ORCID: https://orcid.org/0000-0003-3875-2024)
- Murat K. Saparbaev (ORCID: https://orcid.org/0000-0002-4630-1074)
- Dmitry A. Knorre (ORCID: https://orcid.org/0000-0001-7468-6963)
- Konstantin Gunbin (ORCID: https://orcid.org/0000-0003-1851-8169)
- Konstantin Popadin (ORCID: https://orcid.org/0000-0002-2117-6086)
- Jacques Fellay (ORCID: https://orcid.org/0000-0002-8240-939X)
- Wolfram S. Kunz (ORCID: https://orcid.org/0000-0003-1113-3493)
Institutions
- L. N. Gumilyov Eurasian National University (KZ)
- Northeastern University (US)
- Centre National de la Recherche Scientifique (FR)
- Immanuel Kant Baltic Federal University (RU)
- Xiamen University (CN)
- Lomonosov Moscow State University (RU)
- Université Paris-Saclay (FR)
- University Hospital Bonn (DE)
- Institut Gustave Roussy (FR)
- University of Manchester (GB)
- Institute of Molecular and Cell Biology (RU)
- Research Centre for Medical Genetics (RU)
- Siberian Branch of the Russian Academy of Sciences (RU)
- Moscow State University (TJ)
- École Polytechnique Fédérale de Lausanne (CH)
- Nazarbayev University (KZ)
Publication Details
- Journal
- Molecular Biology and Evolution
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1093/molbev/msae261
- Citations
- 5
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Immanuel Kant Baltic Federal University
- Deutsche Forschungsgemeinschaft
- Russian Science Foundation
- Ministry of Science and Higher Education of the Russian Federation