Exploring the Phenotypic Heterogeneity and Bioenergetic Profile of the m.13513G>A mtDNA Substitution: A Heteroplasmy Perspective
The m.13513G>A (p.Asp393Asn) substitution in the <i>MT-ND5</i> (Mitochondrially Encoded NADH/Ubiquinone Oxidoreductase Core Subunit 5) gene is a common pathogenic variant associated with primary mitochondrial disorders. It frequently causes Leigh syndrome and mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS). In this study, we present clinical data, heteroplasmy levels in various tissues (blood, urine, and skin fibroblasts), and bioenergetic characteristics from a cohort of 20 unrelated patients carrying the m.13513G>A mutation, classified according to the following phenotypes: Leigh syndrome (<i>n</i> = 12), MELAS (<i>n</i> = 2), and Leber's hereditary optic neuropathy (LHON, <i>n</i> = 6). We observed a significant correlation between high respiratory ratios and heteroplasmy levels in fibroblast cell lines of the patients. Furthermore, fibroblast cell lines with heteroplasmy levels exceeding 55% exhibited markedly reduced mitochondrial membrane potential. These findings contribute to a better understanding of the clinical and bioenergetic profiles of patients with m.13513G>A-variant-related phenotypes across different heteroplasmy levels, based on data from a single genetic center. Our data suggest that even a slight shift in heteroplasmy can improve cellular function and, consequently, the patients' phenotype, providing a solid foundation for the development of future gene therapies for mtDNA diseases.
Authors
- Н. А. Андреева (ORCID: https://orcid.org/0000-0001-5626-218X)
- Ekaterina Zakharova (ORCID: https://orcid.org/0000-0002-5020-1180)
- Svetlana Mikhaylova (ORCID: https://orcid.org/0000-0002-2115-985X)
- Д. Д. Елисеева (ORCID: https://orcid.org/0000-0003-2173-927X)
- Е. В. Сайфуллина (ORCID: https://orcid.org/0000-0001-9552-8948)
- Aysylu F. Murtazina (ORCID: https://orcid.org/0000-0001-7023-7378)
- Н Л Шеремет (ORCID: https://orcid.org/0000-0003-4597-4987)
- Konstantin G. Lyamzaev (ORCID: https://orcid.org/0000-0001-9921-8031)
- Peter Sparber (ORCID: https://orcid.org/0000-0002-9160-0794)
- Т. В. Маркова (ORCID: https://orcid.org/0000-0002-2672-6294)
- Natalia V. Buchinskaya (ORCID: https://orcid.org/0000-0002-2335-3023)
- Yu K Murakhovskaya
- Tatiana Krylova (ORCID: https://orcid.org/0000-0002-7197-3497)
- Kistol Denis (ORCID: https://orcid.org/0000-0001-6519-7375)
- G. N. Rudenskaya (ORCID: https://orcid.org/0000-0002-8949-0581)
- Polina Tsygankova (ORCID: https://orcid.org/0000-0003-3998-3609)
- Vyacheslav Tabakov (ORCID: https://orcid.org/0000-0003-0291-153X)
- N.N. Venediktova (ORCID: https://orcid.org/0009-0006-1316-0689)
- Наталя Семенова (ORCID: https://orcid.org/0000-0001-7041-045X)
- Natalia Nikitina (ORCID: https://orcid.org/0000-0002-2811-4718)
- Yulia S. Itkis
- Hasyanya Aksyanova
- Alina Ivanushkina
Institutions
- Sechenov University (RU)
- Lomonosov Moscow State University (RU)
- Pirogov Russian National Research Medical University (RU)
- Nizhny Novgorod Regional Clinical Hospital named after Semashko (RU)
- St. Petersburg State Medical Academy "City Hospital No. 26" (RU)
- Russian Children's Clinical Hospital (RU)
- Ministry of Health of the Russian Federation (RU)
- Bashkir State Medical University (RU)
- Research Centre for Medical Genetics (RU)
- Federal State Scientific Institution Research Institute of Eye Diseases (RU)
- Research Center of Neurology (RU)
- Saint Petersburg State Pediatric Medical University (RU)
Publication Details
- Journal
- International Journal of Molecular Sciences
- Published
- 2025-05-10
- DOI
- https://doi.org/10.3390/ijms26104565
- Citations
- 1
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.81