Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.

ABSTRACT: Mitochondrial diseases, caused by mutations in nuclear or mitochondrial DNA (mtDNA), have limited treatment options. For mtDNA mutations, reducing the mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising strategy, though it currently faces challenges. Previous research showed that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, through changes in DNA methylation, absent or less important for subtle mitochondrial impairment. Therefore, we hypothesized that targeting nuclear DNA methylation could impair cells with high-mutant mtDNA load while sparing those with lower levels, reducing overall heteroplasmy. Using cybrid models harboring two disease-causing mtDNA mutations-m.13513 G > A and m.8344 A > G-at varying heteroplasmies, we discovered t

SUBMITTER: Perez MJ 

PROVIDER: S-EPMC12423320 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature