Expanding insights of mitochondrial dysfunction in Parkinson's disease

Parkinson's disease is the most common neurodegenerative movement disorder, affecting ∼1% of the population above the age of 60. Its pathological hallmarks are the preferential loss of dopaminergic neurons of the substantia nigra pars compacta and formation of Lewy bodies — intracytoplasmic inclusion bodies that are mainly composed of fibrillar α-synuclein.Mitochondrial dysfunction has long been implicated in the pathogenesis of Parkinson's disease, as inhibition of complex I of the mitochondrial electron transport chain and oxidative stress result in dopaminergic cell loss and parkinsonism in vivo.A minority of Parkinson's disease cases are familial, and these have been used to identify 5 genes, α-synuclein, parkin, DJ1 (Parkinson's disease (autosomal recessive, early onset) 7), PINK1 (phosphatase and tensin homologue (PTEN)-induced kinase 1), and LRRK2 (leucine-rich repeat kinase 2) that are causal of the disease. Recently, mutations in a sixth gene, HtrA serine peptidase 2 (HTRA2, also known as OMI) have also been tentatively associated with Parkinson's disease.We critically review how these genes fit into and enhance our understanding of the role of mitochondrial dysfunction in Parkinson's disease and consider how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease.While α-synuclein and parkin mutations indicate that protein misfolding and the ubiquitin–proteasome system (UPS) dysfunction are part of a significant upstream pathway en route to dopaminergic degeneration, the discovery of PINK1, DJ-1 and OMI/HTRA2 mutations confirm that mitochondrial dysfunction is another principle upstream pathway that leads to parkinsonism. As there is considerable crosstalk between these systems, an intriguing question is whether all the known genes converge to a common pathogenetic pathway.The mechanism of how mitochondrial and proteasomal impairment lead to dopamine cell loss is becoming clearer, and the generation of oxidative stress might be common to both. Evidence of increased oxidative damage after mitochondrial or proteasomal impairment has been shown in vivo.There are at least two possible mechanisms: mitochondrial dysfunction that leads to ATP depletion, and oxidative stress that causes UPS dysfunction. Conversely, UPS deregulation results in secondary mitochondrial dysfunction and damage.We discuss how these pathways conspire to cause cell death in Parkinson's disease.