The many faces of mitophagy

Abstract

Failure to maintain mitochondrial integrity is linked to age‐related conditions, such as neurodegeneration. Two genes linked to Parkinson's disease, PINK1 and Parkin, play a key role in targeting the degradation of dysfunctional mitochondria (mitophagy). However, the mechanisms regulating the PINK1/Parkin pathway and other processes that impinge on mitochondrial turnover are poorly understood. Two articles in EMBO reports, by the Przedborski and Ganley groups, shed light on a new role for processed, cytoplasmic PINK1, and show that depletion of cellular iron levels stimulates PINK1/Parkin‐independent mitophagy.

Figure 1. Effects of PINK1 cleavage and low iron on mitophagy

In ‘healthy’ mitochondria with high membrane potential (ΔΨm), PINK1 is imported cleaved by PARL and other proteases, and processed PINK1₅₂ released into the cytosol. Upon mitochondrial damage and loss of ΔΨm, induced in vitro by CCCP or valinomycin, full-length PINK1₆₃ is stabilized on the outer surface and stimulates the recruitment of Parkin, leading to mitophagy. Przedborski and colleagues present evidence that cytoplasmic PINK1₅₂ can inhibit Parkin recruitment. A chemical screen by Ganley and colleagues found that depletion of cellular iron can trigger mitophagy in a new mechanism that does not require PINK1 or Parkin, or the loss of ΔΨm.