Parkin, PINK1 and mitochondrial integrity: emerging concepts of mitochondrial dysfunction in Parkinson's disease
Etiology of Parkinson’s Disease (PD). Sporadic PD is a complex multifactorial disease with variable contributions of environmental factors, such as exposure to toxins and genetic susceptibility. Several polymorphisms have been identified in genome-wide association studies (GWAS) as genetic risk factors for PD, among them polymorphisms in the genes encoding α-synuclein, LRRK2, and tau. Familial forms account for up to 10% of PD cases. Autosomal-dominant parkinsonism is caused by mutations in the genes encoding α-synuclein or LRRK2, whereas mutations in the genes encoding parkin, PINK1, DJ-1, or ATP13A2 are associated with autosomal recessive parkinson.
Mitochondria are dynamic organelles which are essential for many cellular processes, such as ATP production by oxidative phosphorylation, lipid metabolism, assembly of iron sulfur clusters, regulation of calcium homeostasis, and cell death pathways. The dynamic changes in mitochondrial morphology, connectivity, and subcellular distribution are critically dependent on a highly regulated fusion and fission machinery. Mitochondrial function, dynamics, and quality control are vital for the maintenance of neuronal integrity. Indeed, there is mounting evidence that mitochondrial dysfunction plays a central role in several neurodegenerative diseases. In particular, the identification of genes linked to rare familial variants of Parkinson's disease has fueled research on mitochondrial aspects of the disease etiopathogenesis. Studies on the function of parkin and PINK1, which are associated with autosomal recessive parkinsonism, provided compelling evidence that these proteins can functionally interact to maintain mitochondrial integrity and to promote clearance of damaged and dysfunctional mitochondria. In this review we will summarize current knowledge about the impact of parkin and PINK1 on mitochondria.