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

Mitochondrial diseases, caused by mutations in either nuclear or mitochondrial DNA (mtDNA), currently have limited treatment options. For mtDNA mutations, reducing mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising therapeutic option, though current approaches face significant challenges. Previous research has shown that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, characterized by changes in DNA methylation, which does not occur or is less important when mitochondrial impairment is subtle. Building on this, we hypothesized that targeting nuclear DNA methylation could selectively compromise cells with high levels of mutant mtDNA, favor ones with lower mutant load and thereby reduce overall heteroplasmy. EPIC 850k methylation data from cybrids that were obtained from the fusion of the osteosarcoma cell line143B.206 rho0 mtDNA devoid cells with enucleated patient-derived dermal fibroblasts as previously described. The methylome of cybrids harboring wild-type mtDNA and two disease causing mutations: m.13513G>A (´13´ cybrids) and m.8344A>G (´8´cybrids) with high and low heteroplasmy levels was analyzed. Our study reveals a previously unrecognized role for nuclear DNA methylation in regulating cell survival in the context of mitochondrial heteroplasmy. This insight not only advances our understanding of mitochondrial-nuclear interactions but also introduces epigenetic modulation as a possible therapeutic avenue for mitochondrial diseases.