Affiliation:
1. Center for Genetic Medicine the Fourth Affiliated Hospital of School of Medicine and International School of Medicine International institutes of Medicine Zhejiang University Yiwu 322000 China
2. Division of Medical Genetics and Genomics The Children's Hospital Zhejiang University School of Medicine and National Clinical Research Center for Child Health Hangzhou 310058 China
3. Institute of Genetics Zhejiang University International School of Medicine Hangzhou 310058 China
4. Architecture et Réactivité de l'ARN UPR9002 Centre National de la Recherche Scientifique Université de Strasbourg Institut de Biologie Moléculaire et Cellulaire 2 allée Konrad Roentgen Strasbourg 67084 France
Abstract
AbstractLeber's hereditary optic neuropathy (LHON), a maternally inherited ocular disease, is predominantly caused by mitochondrial DNA (mtDNA) mutations. Mitochondrial tRNA variants are hypothesized to amplify the pathogenic impact of three primary mutations. However, the exact mechanisms remained unclear. In the present study, the synergistic effect of the tRNAGlu 14693A > G and ND6 14484T > C mutations in three Chinese families affected by LHON is investigated. The m.14693A > G mutation nearly abolishes the pseudouridinylation at position 55 of tRNAGlu, leading to structural abnormalities, decreased stability, aberrant mitochondrial protein synthesis, and increased autophagy. In contrast, the ND6 14484T > C mutation predominantly impairs complex I function, resulting in heightened apoptosis and virtually no induction of mitochondrial autophagy compared to control cell lines. The presence of dual mutations in the same cell lines exhibited a coexistence of both upregulated cellular stress responses to mitochondrial damage, indicating a scenario of autophagy and mutation dysregulation within these dual‐mutant cell lines. The data proposes a novel hypothesis that mitochondrial tRNA gene mutations generally lead to increased mitochondrial autophagy, while mutations in genes encoding mitochondrial proteins typically induce apoptosis, shedding light on the intricate interplay between different genetic factors in the manifestation of LHON.
Funder
National Natural Science Foundation of China