Mitochondrial dysfunction and mitophagy in Parkinson's: from familial to sporadic disease

• A number of biochemical perturbations in Parkinson's disease (PD) are linked to mitochondrial dysfunction.
• Progress in 2014 has defined new mechanisms of PINK1 and parkin-dependent mitophagy.
• α-Synuclein (α-syn) levels and aggregation link mitochondria to familial and sporadic PD.
• These new insights suggest novel mechanisms and therapeutic targets in PD.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the preferential loss of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuronal susceptibility in PD and is a feature of both familial and sporadic disease, as well as in toxin-induced Parkinsonism. Recently, the mechanisms by which PD-associated mitochondrial proteins phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (PINK1) and parkin function and induce neurodegeneration have been identified. In addition, increasing evidence implicates other PD-associated proteins such as α-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) in mitochondrial dysfunction in genetic cases of PD with the potential for a large functional overlap with sporadic disease. This review highlights how recent advances in understanding familial PD-associated proteins have identified novel mechanisms and therapeutic strategies for addressing mitochondrial dysfunction in PD.