Insights in POLG-related disorders: a drug repurposing trial on newly generated POLG and POLG2 zebrafish mutant lines

POLG-related disorders are a wide group of rare genetic conditions with overlapping phenotypes. They are mostly inherited in an autosomal recessive manner, and heterozygotes are generally believed to be asymptomatic. The clinical manifestations arise from the progressive depletion or accumulation of errors in mitochondrial DNA (mtDNA), leading to defects in oxidative-phosphorylation in high energy-consuming districts such as muscle and neuronal tissues. The molecular mechanisms underlying these disorders are not well understood, but they appear to be linked to mutations in POLG and POLG2 genes, which encode for the DNA polymerase γ: the only polymerase responsible for replication, repair and recombination of mtDNA. Newly generated POLG and POLG2 zebrafish mutant lines have been exploited to investigate the efficacy of candidate drugs that showed an improvement in the pathophysiology of POLG mutant yeast cells. The aim of this study is to conduct a drug repurposing trial with these drugs (Auranofin, Bepridil, Clofilium tosylate, Diethylstilbestrol, Imazalil, Ebselen, Ibutilide, and Dofetilide) to achieve promising results that could serve as a solid foundation for future clinical applications.