Role of PINK1 Binding to the TOM Complex and Alternate Intracellular Membranes in Recruitment and Activation of the E3 Ligase Parkin

Lazarou, Michael; Jin, Seok Min; Kane, Lesley A.; Youle, Richard J.

doi:10.1016/j.devcel.2011.12.014

Cited by 571 publications

(565 citation statements)

References 54 publications

Supporting

Mentioning

527

Contrasting

Unclassified

Order By: Relevance

“…Presumably, as a kinase, Pink1 can phosphorylate some mitochondrial surface proteins or itself serve as an anchor for Parkin. The possibility that there are unique mitochondrial anchors has been ruled out by a recent study: when Pink1 is ectopically targeted to peroxisomes, Parkin is redirected to peroxisomes and, interestingly, it induces their autophagy [21]. In line with this observation, Pink1 has been shown to interact with Parkin [22].…”

Section: Introductionsupporting

confidence: 59%

Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism

Zheng

Hunter

2013

Cell Res

View full text Add to dashboard Cite

Pink1, a mitochondrial kinase, and Parkin, an E3 ubiquitin ligase, function in mitochondrial maintenance. Pink1 accumulates on depolarized mitochondria, where it recruits Parkin to mainly induce K63-linked chain ubiquitination of outer membrane proteins and eventually mitophagy. Parkin belongs to the RBR E3 ligase family. Recently, it has been proposed that the RBR domain transfers ubiquitin to targets via a cysteine~ubiquitin enzyme intermediate, in a manner similar to HECT domain E3 ligases. However, direct evidence for a ubiquitin transfer mechanism and its importance for Parkin's in vivo function is still missing. Here, we report that Parkin E3 activity relies on cysteinemediated ubiquitin transfer during mitophagy. Mutating the putative catalytic cysteine to serine (Parkin C431S) traps ubiquitin, and surprisingly, also abrogates Parkin mitochondrial translocation, indicating that E3 activity is essential for Parkin translocation. We found that Parkin can bind to K63-linked ubiquitin chains, and that targeting K63-mimicking ubiquitin chains to mitochondria restores Parkin C431S localization. We propose that Parkin translocation is achieved through a novel catalytic activity coupled mechanism.

show abstract

Section: Introductionsupporting

confidence: 59%

Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism

Zheng

Hunter

2013

Cell Res

View full text Add to dashboard Cite

show abstract

“…We have recently identified Mtx2 and 1 as receptors for Bak during TNFα/CHX induced apoptosis (6). Quite interestingly, recent results have shown that TOM machinery is essential in the mitochondrial elimination during autophagy by controlling the PINK-PARK pathway (25,26). These results confirm that mitochondrial protein import machineries are implicated in cell survival not only through regulation of metabolism but also though the control of cell death programs.…”

Section: Discussionsupporting

confidence: 69%

The phosphorylation of Metaxin 1 controls Bak activation during TNFα induced cell death

Petit

Cartron

Oliver

et al. 2017

Cellular Signalling

View full text Add to dashboard Cite

International audienceThe proapoptotic protein Bak is implicated in the execution phase of apoptosis, a cell death program. Bak is essentially mitochondrial and during early steps of apoptosis undergoes conformational changes that lead to its full membrane integration in mitochondria and the subsequent liberation of pro-apoptotic mitochondrial proteins. Little is known about the partners and mechanisms implicated in the activation of Bak. We have recently shown that Bak is incorporated into a Voltage dependent anionic channel of type 2 (VDAC2)/Metaxin 1(Mtx1)/Metaxin 2 (Mtx2) multi-protein complex in both resting and dying cells. Here, we show that, after the induction of apoptosis, Bak switches from its association with Mtx2 and VDAC2 to a closer association with Mtx1. This change of partners is under the control of a tyrosine phosphorylation of Mtx1 by c-Abl

show abstract

“…[70][71][72][73] Loss of mitochondrial membrane potential may be the event that acutely activates this pathway; loss of the potential gradient precludes import of PINK1 to the inner membrane, thereby stabilizing intact PINK1 on the mitochondrial outer membrane where it interacts with the TOM complex. 74 In this manner, PINK1 serves as a sensor for mitochondrial damage. Accumulation of PINK1 on the mitochondrial surface induces translocation of Parkin from the cytosol to damaged mitochondria through a mechanism as yet unknown.…”

Section: The Pink1/parkin Pathway Of Mitophagymentioning

confidence: 99%

“…This hypothesis is consistent with the ability of Parkin ectopically targeted to peroxisomes to mediate surface ubiquitination and autophagic degradation of these organelles. 74 In summary, while the ubiquitin ligase activity of Parkin is well established, further work is required to determine how Parkin-mediated ubiquitination promotes mitophagy.…”

Section: Parkin Promotes Ubiquitination Of Mitochondrial Proteinsmentioning

confidence: 99%

“…35,71 In addition, PINK1 artificially targeted to peroxisomal membranes can recruit Parkin and mediate autophagic degradation of the peroxisome. 74 Thus, PINK1 and Parkin form the minimal machinery for recruitment of the canonical autophagy players to target organelles. Although the kinase activity of PINK1 is required for it to recruit Parkin, it is unclear as to how this occurs.…”

Section: The Pink1/parkin Pathway Of Mitophagymentioning

confidence: 99%

See 1 more Smart Citation

The pathways of mitophagy for quality control and clearance of mitochondria

2012

View full text Add to dashboard Cite

Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration. Facts Mitophagy mediates clearance of damaged mitochondria, and is also involved in the removal of mitochondria from maturing erythrocytes and eliminating sperm-derived mitochondria after fertilization. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the core autophagic machinery to mitochondria for their selective removal. A pathway containing PTEN-induced putative protein kinase 1 (PINK1) and Parkin responds to loss of mitochondrial membrane potential by targeting damaged mitochondria for clearance. The PINK1/Parkin pathway is triggered when PINK1 is stabilized on the outer membrane of damaged mitochondria, where it facilitates recruitment of cytosolic Parkin. Damaged mitochondria are prevented from moving and fusing with the mitochondrial reticulum in preparation for their mitophagic clearance. Open QuestionsHow distinct are the mitophagy pathways triggered by different stimuli or conditions?To what extent does Parkin activate mitophagy by causing the degradation of mitochondrial surface proteins or hyperubiquitinating the mitochondrial surface? How do PINK1 and Parkin interact with one another and with substrates on the mitochondrial surface in causing mitophagy? In contrast to the remarkable conservation of the core autophagic machinery, why are mitophagy-specific genes so little conserved between yeast and mammals? How best should mitophagy be triggered by researchers probing physiologically relevant pathways?The mitochondrion is an important actor in the life of a eukaryotic cell, but, like all good actors, a mitochondrion needs to exit the stage at the right time. Mitophagy removes mitochondria once they have played their part. This artic...

show abstract

Role of PINK1 Binding to the TOM Complex and Alternate Intracellular Membranes in Recruitment and Activation of the E3 Ligase Parkin

Cited by 571 publications

References 54 publications

Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism

Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism

The phosphorylation of Metaxin 1 controls Bak activation during TNFα induced cell death

The pathways of mitophagy for quality control and clearance of mitochondria

Contact Info

Product

Resources

About