Editors' ChoiceCell Biology

Parkin Can Promote Apoptosis

Sci. Signal.  26 Aug 2014:
Vol. 7, Issue 340, pp. ec228
DOI: 10.1126/scisignal.2005831

PTEN-induced kinase 1 (Pink1) acts upstream of the ubiquitin ligase Parkin to control the dynamics and degradation of mitochondria. Pink1 accumulates on damaged or dysfunctional mitochondria, where it recruits and activates Parkin to promote mitochondrial repair or mitophagy. Mutations in Parkin are associated with Parkinson’s disease, which involves the loss of dopaminergic neurons that are particularly sensitive to excitotoxic stress. Zhang et al. report that Pink1-mediated activation of Parkin also stimulates cell death in response to irreparable mitochondrial damage. HeLa cells stably expressing wild-type Parkin responded to the mild mitochondrial-damaging agent carbonyl cyanide m-chlorophenyl hydrazone (CCCP) with mitophagy to remove the dysfunctional mitochondria. CCCP did not induce mitophagy in HeLa cells stably expressing a mutant version of Parkin that is associated with familial early-onset Parkinson’s disease. In contrast, HeLa cells stably expressing wild-type Parkin responded to the potassium ionophore valinomycin, which causes more severe mitochondrial dysfunction than agents like CCCP, by undergoing apoptosis. Cells expressing mutant Parkin survived valinomycin treatment. Valinomycin-triggered apoptosis was Pink1-dependent and characterized by a gradual decline in the abundance of the antiapoptotic protein Mcl-1 over a period of several hours. The abundance of Mcl-1 was unaffected in valinomycin-treated cells expressing the mutant form of Parkin or in cells exposed to CCCP. Human Pink1 was not catalytically active in vitro, but an insect homolog of Pink1 that is active in vitro, TcPink1, phosphorylated Ser65 in the ubiquitin-like domain of rat Parkin (rParkin) and Ser65 of ubiquitin in vitro. Nonphosphorylated, but highly purified, rParkin ubiquitylated Mcl-1 in vitro, but a catalytically inactive mutant form of rParkin did not. Ser65 phosphorylation of both rParkin and ubiquitin enhanced the ubiquitylation of Mcl-1 in vitro. Expression of a S65A mutant form of Parkin blocked valinomycin-induced apoptosis in HeLa cells and mouse embryonic fibroblasts. These findings indicate that, in addition to inducing mitophagy in response to mitochondrial damage, Parkin can also promote cell death when mitochondrial damage is irreparable. How different types or degrees of mitochondrial damage influence the substrate specificity of Parkin remains an open question.

C. Zhang, S. Lee, Y. Peng, E. Bunker, E. Giaime, J. Shen, Z. Zhou, X. Liu, PINK1 triggers autocatalytic activation of Parkin to specify cell fate decisions. Curr. Biol. 24, 1854–1865 (2014). [PubMed]