PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage

Abstract

Mutations in the PINK1 gene are a frequent cause of autosomal recessive Parkinson's disease (PD). PINK1 encodes a mitochondrial kinase with neuroprotective activity, implicated in maintaining mitochondrial homeostasis and function. In concurrence with Parkin, PINK1 regulates mitochondrial trafficking and degradation of damaged mitochondria through mitophagy. Moreover, PINK1 can activate autophagy by interacting with the pro-autophagic protein Beclin-1. Here, we report that, upon mitochondrial depolarization, PINK1 interacts with and phosphorylates Bcl-xL, an anti-apoptotic protein also known to inhibit autophagy through its binding to Beclin-1. PINK1-Bcl-xL interaction does not interfere either with Beclin-1 release from Bcl-xL or the mitophagy pathway; rather it protects against cell death by hindering the pro-apoptotic cleavage of Bcl-xL. Our data provide a functional link between PINK1, Bcl-xL and apoptosis, suggesting a novel mechanism through which PINK1 regulates cell survival. This pathway could be relevant for the pathogenesis of PD as well as other diseases including cancer. Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, with prevalence of 1% in the population older than 60 years. 1 Several biochemical abnormalities, including mitochondrial dysfunction, oxidative stress and misfolded protein damage, have been implicated in PD pathogenesis. 2 Although the majority of late-onset cases are sporadic, early-onset PD is frequently caused by mutations in genes with autosomal recessive inheritance, mainly Parkin (GeneID: 5071) and PINK1 (GeneID: 65018). 3 PINK1 encodes a 63 kDa mitochondrial protein kinase, which is processed by mitochondrial proteases to generate two smaller isoforms. [4][5][6][7] We and others have shown that PINK1 acts as a key neuroprotective protein, aimed at preventing mitochondrial dysfunction and apoptotic cell death in response to multiple stress conditions. [8][9][10] This pro-survival activity is exerted through several mechanisms, including phosphorylation of the mitochondrial proteins TRAP1 and Omi/HtrA2, and regulation of mitochondrial calcium buffering. [11][12][13][14] Increasing data now indicate that PINK1 acts upstream of Parkin in an evolutionary conserved pathway implicated in regulating mitochondrial biogenesis, trafficking and fusion/ fission events, to maintain mitochondrial network health. 15 In particular, upon mitochondrial depolarization, PINK1 processing is impaired, determining a marked accumulation of the full-length protein on the surface of dysfunctional mitochondria, where it recruits Parkin. This process results in the phosphorylation and/or ubiquitination of several mitochondrial substrates, leading to the selective quarantine of damaged mitochondria and their degradation through mitophagy. [16][17][18][19] In line with this, we reported that coexpression of mutant, but not wild-type (wt) PINK1, with mutant alpha-synuclein resulted in the formation of enlarged autophagosomes surrounding abnormal mitoch...

PINK1 signalling in cancer biology

“…Research during the past decade demonstrates that PINK1 has major pro-survival, anti-apoptotic and cytoprotective functions [35][36][37][38][39][40][41][42][43][44]. These properties of PINK1 have been shown to be implemented by both mitochondrial and cytosolic functions of PINK1, and mechanistically through proteasomal [45][46][47] and autophagic [48,49] pathways, and via PI3-kinase/Akt/mTOR [37,41,50,51], NFκB [52,53] and calcium dependent signalling [54][55][56].…”

“…PINK1 recruitment to depolarised mitochondria has also been shown to protect from cell death in cancer cells by phosphorylation of the major pro-survival protein Bcl-xL, preventing Bcl-xL's proapoptotic cleavage, and described to be independent of mitophagy [36]. Further, PINK1 deletion reduces Bcl-xL and increases BAX protein expression in bladder cancer cells, linked to their partial sensitisation to cell death [73].…”

Dysfunction of autophagy as the pathological mechanism of motor neuron disease based on a patient-specific disease model

“…PS-1 mutation interferes with the acidification of lysosomes and leads to impaired cargo clearance by autophagolysosomes. Similarly, many PD-associated genes, such as PINK1, Parkin, and LRRK2, have also been found to interact with Beclin1, and their mutant forms can alter the induction of PD and may contribute to its progress [25][26][27] . As a matter of fact, treatment with rapamycin, which enhances autophagic activity, can improve the symptoms of several neurodegenerative diseases including AD, PD, and HD [20,28] .…”

Phospho-Bcl-xL(Ser62) influences spindle assembly and chromosome segregation during mitosis

“…Some have suggested that Bcl-xL phosphorylation maintains its anti-apoptotic function, 19 while others have reported that phosphorylation causes Bcl-xL to release bound Bax and promote apoptosis 27 . More recently, others have suggested that Bcl-xL phosphorylation impaired its pro-apoptotic N-terminal cleavage 28 . No one has investigated other possible Bcl-xL functions directly impacting mitosis regulation and progression.…”