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

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. 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 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. the major component of Lewy bodies and a protein with diverse roles in cellular biology; mutations in α-synuclein increase the propensity for the protein to aggregate and cause autosomal dominant familial PD. a mitochondrial protein and familial PD risk gene that regulates mitochondrial function. a protonophore and a potent mitochondrial uncoupler that depolarises the mitochondrial membrane and induces mitophagy; CCCP is used extensively in the study of PINK1/Parkin-dependent mitophagy neurons that release the neurotransmitter dopamine; the midbrain dopaminergic neurons in the substantia nigra pars compacta (SNpc) are preferentially vulnerable in PD, whereas the neighbouring dopaminergic neurons of the VTA are relatively spared. a large group of proteins that remove ubiquitin (Ub) chains from proteins; DUBs, such as USP8, USP14, USP15, USP35, and most prominently USP30, have been found to regulate mitophagy by antagonising parkin activity. a widely expressed multidomain kinase; mutations in LRRK2 are the most common form of autosomal dominant PD. intracellular protein aggregates comprising misfolded proteins, of which α-synuclein is a prominent component; Lewy bodies are the defining pathological feature of postmortem PD brain form of selective autophagy targeting damaged mitochondria making use of two major degradation systems: autophagy and the ubiquitin-proteasome system; mitophagy acts as a mitochondrial quality-control mechanism. an E3 Ub ligase catalysing the attachment of Ub chains to substrate proteins; after activation by PINK1, parkin ubiquitinates outer mitochondrial membrane proteins and mediates the clearance of damaged mitochondria; mutations in PRKN cause autosomal recessive PD. a progressive, neurodegenerative disease characterised by both motor and non-motor symptoms; pathologically, the disease is characterised by the aggregation of α-synuclein into Lewy bodies and the preferential degeneration of dopaminergic neurons of the SNpc. PINK1 phosphorylates the serine 65 residue on Ub chains on the OMM, forming pSer65Ub; pSer65Ub has a crucial role in the amplification of the PINK1/parkin pathway. a serine/threonine-protein kinase with a central role in mitophagy following mitochondrial membrane depolarisation phosphorylating both parkin and Ub; mutations in PINK1 cause autosomal recessive PD. the dopaminergic nigrostriatal neurons arising from the SNpc release dopamine in the striatum modulating motor activity; the SNpc A9 region is the major site of dopaminergic neuron loss in PD. a complex of proteins (e.g., TOM20 and TOM40) that regulate protein transport across the OMM. degradation of mitochondria in a noncell-autonomous manner (e.g., by glial cells). a small protein that can post-translationally modify proteins, influencing their function and targeting them for degradation. a dopaminergic region of the midbrain neighbouring the SNpc. The VTA A10 dopaminergic neurons are relatively spared in PD.