mtDNA maintenance: disease and therapy

Abstract Mitochondrial maintenance disorders present as a spectrum ranging from severe infantile multisystemic syndrome to childhood or adult tissue-specific diseases. Hallmark is the variable association of qualitative (point mutations, multiple deletions) or quantitative (copy number reduction) molecular genetic defect of mitochondrial DNA (mtDNA), biochemical dysfunction with multiple OXPHOS defects and morphological alterations of the mitochondrial network. Therapies for mitochondrial disorders, targeting pathogenic mechanism with “general” or “disease tailored” action, have been successfully experimented in in vitro and in vivo studies. Preclinical evidence of efficacy and safety has led for some of them to the translation into clinical trials. Those are specifically available for treatment in mtDNA maintenance disorders, bringing the hope to find a definitive cure in the immediate future. In this chapter, we will present an overview of the clinical syndrome in the mtDNA replication pathway and will elucidate the potential application of pharmacological approaches with general action to mtDNA maintenance disorders by analyzing compounds increasing mitochondrial biogenesis or modulating mTOR pathway. In addition, we will explore supplementation of nucleosides, clearance of toxic metabolites and enzyme replacement therapies in enzymatic deficiencies and gene therapy approaches in the same pathway.