Phosphatase and Tensin Homolog (PTEN)-induced Putative Kinase 1 (PINK1)-dependent Ubiquitination of Endogenous Parkin Attenuates Mitophagy

Abstract

Background:The Parkinson disease-related proteins PINK1 and Parkin initiate mitophagy of damaged mitochondria. Results: Endogenous Parkin is not sufficient to induce mitophagy due to PINK1-dependent ubiquitination of Parkin. Conclusion: Mitophagy is detectable only with supraphysiological levels of Parkin and differs between fibroblasts and iPSderived neurons. Significance: Stresses the importance of future studies in Parkinson disease-relevant tissue, i.e., dopaminergic neurons.

Parkin-catalyzed Ubiquitin-Ester Transfer Is Triggered by PINK1-dependent Phosphorylation

“…As a consequence, damaged mitochondria are quarantined by decreased mitochondrial fusion, separated from the destination by a pause in kinesin-dependent trafficking, and/or degraded via autophagy. The final destination of low-quality mitochondria remains controversial (11,(17)(18)(19)(20)(21)(22)(23). Furthermore, PINK1 may also possess alternative functions other than Parkin recruitment (24,25).…”

A Dimeric PINK1-containing Complex on Depolarized Mitochondria Stimulates Parkin Recruitment

“…PINK1 simultaneously forms a high molecular weight complex with the translocase of the outer membrane (TOM) machinery (18). The ubiquitin ligase (E3) Parkin, another causal gene in autosomal recessive early onset parkinsonism (19,20), is subsequently recruited to the depolarized mitochondria and functions in the sequestration and/or elimination of damaged mitochondria in cultured cells (21), iPS-derived neurons (1,22,23), and mouse primary neurons (24 -26). PINK1 is essential for recruiting Parkin to the depolarized mitochondria; thus, it acts as an upstream factor of Parkin (15,16,(27)(28)(29)(30).…”

Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance

“…Although Parkin overexpression in cultured cells can effectively eliminate the majority of mitochondria on depolarizing stress, endogenous Parkin levels are not sufficient to mediate mitophagy in many cell types including murine embryonic fibroblasts (MEFs) 23,24 , which, similar to Parkin knockout cells, do not exhibit mitochondrial aberrations that are indicative of defects in mitochondrial surveillance [25][26][27][28] . Thus, the physiological role of Parkin-mediated mitophagy in mitochondrial homeostasis is not fully understood 14,29,30 .…”