Mitochondria play key roles in the cellular metabolism of lipids and iron as well as in cell death signaling. Mitochondrial dysregulation produces reactive oxygen species (ROS), which results in oxidative stress. Moreover, the accumulation of damaged mitochondria leads to cell death and tissue dysfunction. Mitochondrial maintenance involves mitophagy, a selective autophagy process that removes abnormal mitochondria. Parkinson’s disease (PD) is a movement disorder caused by the specific loss of dopaminergic neurons in the substantia nigra of the midbrain. Two genes implicated in PD, PINK1 and Parkin, regulate mitophagy in cultured cells. Reduction of the ΔΨm leads to activation of PINK1, which stimulates the recruitment of Parkin to the mitochondrial outer membrane of damaged mitochondria and activates Parkin’s ubiquitin-ligase activity. Activated mitochondrial Parkin leads to the ubiquitination of mitochondrial proteins and subsequent mitophagy. This elaborate molecular mechanism was recently uncovered and the findings demonstrate the physiological and pathological roles of the PINK1-Parkin pathway. Here, we review these key findings on the molecular mechanism and ideas relevant to neurodegeneration caused by dysregulation of the PINK1-Parkin pathway.
Part of the book: Cell Death