This study investigates the mechanism by which PINK1 and Parkin function together to protect against mitochondrial damage. PINK1 is a mitochondrial kinase that accumulates selectively on dysfunctional mitochondria with low membrane potential, while Parkin is an E3 ubiquitin ligase that recruits to these mitochondria to trigger their autophagic degradation. The authors show that PINK1 accumulation on mitochondria is regulated by voltage-dependent proteolysis, maintaining low levels on healthy mitochondria while facilitating rapid accumulation on damaged mitochondria. This accumulation of PINK1 recruits Parkin, which then induces the degradation of the damaged mitochondria. Disease-causing mutations in PINK1 or Parkin disrupt this pathway at distinct steps, leading to impaired mitophagy and mitochondrial dysfunction. The findings provide a biochemical explanation for the genetic epistasis between PINK1 and Parkin in *Drosophila melanogaster* and support a novel model for the negative selection of damaged mitochondria.This study investigates the mechanism by which PINK1 and Parkin function together to protect against mitochondrial damage. PINK1 is a mitochondrial kinase that accumulates selectively on dysfunctional mitochondria with low membrane potential, while Parkin is an E3 ubiquitin ligase that recruits to these mitochondria to trigger their autophagic degradation. The authors show that PINK1 accumulation on mitochondria is regulated by voltage-dependent proteolysis, maintaining low levels on healthy mitochondria while facilitating rapid accumulation on damaged mitochondria. This accumulation of PINK1 recruits Parkin, which then induces the degradation of the damaged mitochondria. Disease-causing mutations in PINK1 or Parkin disrupt this pathway at distinct steps, leading to impaired mitophagy and mitochondrial dysfunction. The findings provide a biochemical explanation for the genetic epistasis between PINK1 and Parkin in *Drosophila melanogaster* and support a novel model for the negative selection of damaged mitochondria.