Mitochondrial Dysfunction and Mitophagy in Parkinson’s Disease: From Mechanism to Therapy

Mitochondrial dysfunction has been associated with neurodegeneration in Parkinson’s disease (PD) for over 30 years. Despite this, the role of mitochondrial dysfunction as an initiator, propagator, or bystander remains undetermined. The discovery of the role of the PD familial genes PTEN-induced putative kinase 1 (PINK1) and parkin (PRKN) in mediating mitochondrial degradation (mitophagy) reaffirmed the importance of this process in PD aetiology. Recently, progress has been made in understanding the upstream and downstream regulators of canonical PINK1/parkin-mediated mitophagy, alongside noncanonical PINK1/parkin mitophagy, in response to mitochondrial damage. Progress has also been made in understanding the role of PD-associated genes, such as SNCA, LRRK2, and CHCHD2, in mitochondrial dysfunction and their overlap with sporadic PD (sPD), opening opportunities for therapeutically targeting mitochondria in PD. Mitochondrial dysfunction is implicated in PD through both environmental exposure and genetic factors. Increased understanding of mitochondrial dysfunction and mitophagy in PD has identified new mechanisms and therapeutic opportunities.Identification of the up- and downstream regulators of PINK1/parkin-dependent mitophagy has highlighted tight regulation of ubiquitin phosphorylation as well as roles of parkin independent of PINK1.There has been increased understanding of the mitochondrial roles of familial PD genes such as the disruption of mitophagy by LRRK2 mutations and observations that α-synuclein oligomers and aggregates interact with outer mitochondrial membrane substrates, inducing mitochondrial dysfunction.Recent studies of large numbers of patients with sPD demonstrated peripheral mitochondrial and lysosomal dysfunction, and, importantly, overlaps with phenotypes observed in familial disease.Enhanced understanding of the mechanisms regulating mitophagy and the causes of mitochondrial dysfunction in PD have led to a range of novel therapeutic opportunities.