Exactly how PINK1 and Parkin work together to protect against damaged mitochondria is unclear. Previous studies in flies and mice, and in human cells suggest that PINK1 and Parkin are part of a common pathway that protects against damaged mitochondria these organelles power the cell when healthy but can produce harmful reactive oxygen species when damaged. ![]() Understanding how the products of these genes work may give us insights into what goes wrong in these patients and in Parkinson disease more generally. Mutations in the PINK1 or Parkin genes lead to an inherited form of Parkinson disease. ![]() In addition, they support a novel model for the negative selection of damaged mitochondria, in which PINK1 signals mitochondrial dysfunction to Parkin, and Parkin promotes their elimination. These findings provide a biochemical explanation for the genetic epistasis between PINK1 and Parkin in Drosophila melanogaster. ![]() PINK1 accumulation on mitochondria is both necessary and sufficient for Parkin recruitment to mitochondria, and disease-causing mutations in PINK1 and Parkin disrupt Parkin recruitment and Parkin-induced mitophagy at distinct steps. Here, we show that expression of PINK1 on individual mitochondria is regulated by voltage-dependent proteolysis to maintain low levels of PINK1 on healthy, polarized mitochondria, while facilitating the rapid accumulation of PINK1 on mitochondria that sustain damage. How Parkin recognizes damaged mitochondria, however, is unknown. Parkin is selectively recruited from the cytosol to damaged mitochondria to trigger their autophagy. ![]() Loss-of-function mutations in PINK1 and Parkin cause parkinsonism in humans and mitochondrial dysfunction in model organisms.
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