Potential Therapies for Mitochondrial Diseases Caused by mtDNA Mutations

Abstract

Mitochondrial diseases, caused by mutations in mitochondrial DNA (mtDNA), present significant genetic and clinical complexities that challenge accurate diagnosis and treatment. This review examines the critical molecular mechanisms underlying these disorders, particularly the role of heteroplasmy, where mixtures of mutated and normal mtDNA influence disease severity, and the nuclear-mitochondrial DNA interactions that compound diagnostic and therapeutic challenges. The threshold effect, wherein clinical symptoms manifest only when mutant mtDNA exceeds a critical proportion, exemplifies the complexity of genotype-phenotype correlations in these conditions. We analyze recent advancements in therapeutic strategies, including targeted small molecule treatments designed to enhance mitochondrial function and restore Nicotinamide Adenine Dinucleotide (NAD+) levels, which have demonstrated efficacy in preclinical models. Additionally, we explore emerging gene therapy approaches that aim to directly correct mtDNA mutations, representing innovative strategies with potential for definitive treatment. This review provides comprehensive insights into the interplay between genetic mechanisms and therapeutic innovations, emphasizing the critical need for translational research. By elucidating the molecular mechanisms driving mitochondrial diseases, we aim to inform development of targeted therapies and improve clinical outcomes for affected patients.