Mitochondrial DNA homeostasis impairment and dopaminergic dysfunction: A trembling balance

Maintenance of mitochondrial DNA (mtDNA) homeostasis includes a variety of processes, such as mtDNA replication, repair, and nucleotides synthesis, aimed at preserving the structural and functional integrity of mtDNA molecules. Mutations in several nuclear genes (i.e., POLG, POLG2, TWNK, OPA1, DGUOK, MPV17, TYMP) impair mtDNA maintenance, leading to clinical syndromes characterized by mtDNA depletion and/or deletions in affected tissues. In the past decades, studies have demonstrated a progressive accumulation of multiple mtDNA deletions in dopaminergic neurons of the substantia nigra in elderly population and, to a greater extent, in Parkinson's disease patients. Moreover, parkinsonism has been frequently described as a prominent clinical feature in mtDNA instability syndromes. Among Parkinson's disease-related genes with a significant role in mitochondrial biology, PARK2 and LRRK2 specifically take part in mtDNA maintenance. Moreover, a variety of murine models (i.e., "Mutator", "MitoPark", "PD-mitoPstI", "Deletor", "Twinkle-dup" and "TwinkPark") provided in vivo evidence that mtDNA stability is required to preserve nigrostriatal integrity. Here, we review and discuss the clinical, genetic, and pathological background underlining the link between impaired mtDNA homeostasis and dopaminergic degeneration.