In this issue of the JCI, Xiong et al. report that Pink1, Parkin, and DJ-1 bind to each other and form a PPD E3 ligase complex in which Pink1 and DJ-1 modulate Parkin-dependent ubiquitination and subsequent degradation of substrates via the proteasome (26). Previous work suggests that the Pink1/Parkin pathway regulates mitochondrial integrity and promotes mitochondrial fission in Drosophila (9–14). (A) Parkin and DJ-1 may be recruited to the mitochondrial outer membrane during stress (30, 31) and interact with Pink1. These interactions may facilitate the ligase activity of Parkin, thereby facilitating the turnover of molecules that regulate mitochondrial dynamics and mitophagy. The PPD complex may have other roles in the cytosol that result in degradative ubiquitination (26) and/or relay information from mitochondria to other cellular compartments. (B) Alternatively, Pink1 may be released from mitochondria after cleavage to interact with DJ-1 and Parkin in the cytosol. A and B differ in the site of action of the PPD complex and the cleavage status of Pink1. The complex forms on the mitochondrial outer membrane potentially containing full-length Pink1 in A, and in the cytosol with cleaved Pink1 in B. The question marks indicate speculative connections. Note that lack of DJ-1 function results in phenotypes that are distinct from the mitochondrial phenotypes observed in null mutants of Pink1 or Parkin in Drosophila (9, 10, 12, 13, 34). Thus, although the PPD complex is illustrated here as regulating mitochondrial fission, the role of DJ-1 in vivo remains to be clarified. (C) It is also possible that the action occurs in the cytosol and is independent of the function of Pink1/Parkin in regulating mitochondrial integrity and function.