Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients

Raković, Aleksandar; Grünewald, Anne; Seibler, Philip; Ramı́rez, Alfredo; Kock, Norman; Orolicki, Slobodanka; Lohmann, Katja; Klein, Christine

doi:10.1093/hmg/ddq215

Cited by 115 publications

(123 citation statements)

References 44 publications

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“…Pink1 was found to be essential for Parkin translocation to mitochondria [10,[15][16][17][18][19]. Pink1 import into mitochondria was shown to be sensitive to mitochondrial membrane potential.…”

Section: Introductionmentioning

confidence: 98%

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

Zheng

Hunter

2013

Cell Res

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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.

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Section: Introductionmentioning

confidence: 98%

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

Zheng

Hunter

2013

Cell Res

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“…The discovery of mutations in the genes encoding the PTEN-induced putative kinase-1 (PINK1) and Parkin, which are linked to rare familial forms of PD, has led to the hypothesis that a defect in mitochondrial quality control may contribute to PD [2]. Upon reduction of the mitochondrial membrane potential (DΨ m ) by chemicals such as Carbonyl cyanide m-chlorophenyl hydrazone (CCCP) or valinomycin, cytosolic Parkin translocates to the mitochondria [3] in a PINK1-dependent manner [4][5][6][7][8][9]. Once the mitochondria are decorated with Parkin, they cluster and migrate toward the perinuclear area of the cell where they co-localize with autophagy/lysosomal markers [4,5].…”

Section: Introductionmentioning

confidence: 99%

Cytosolic cleaved PINK 1 represses P arkin translocation to mitochondria and mitophagy

Fedorowicz

Vries‐Schneider

Rüb³

et al. 2013

EMBO Reports

102

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PINK1 is a mitochondrial kinase proposed to have a role in the pathogenesis of Parkinson's disease through the regulation of mitophagy. Here, we show that the PINK1 main cleavage product, PINK1 52, after being generated inside mitochondria, can exit these organelles and localize to the cytosol, where it is not only destined for degradation by the proteasome but binds to Parkin. The interaction of cytosolic PINK1 with Parkin represses Parkin translocation to the mitochondria and subsequent mitophagy. Our work therefore highlights the existence of two cellular pools of PINK1 that have different effects on Parkin translocation and mitophagy.

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“…Targeting of Parkin to mitochondria requires PTEN-induced putative kinase 1 (Pink1), 3 another Parkinson disease-associated gene product (7)(8)(9)(10)(11)(12)(13)(14). Pink1 is an extremely unstable mitochondrial protein, but it is stabilized upon mitochondrial depolarization and subsequently recruits Parkin.…”

mentioning

confidence: 99%

Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane

Yoshii

Kishi

Ishihara

et al. 2011

Journal of Biological Chemistry

551

463

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Upon mitochondrial depolarization, Parkin, a Parkinson disease-related E3 ubiquitin ligase, translocates from the cytosol to mitochondria and promotes their degradation by mitophagy, a selective type of autophagy. Here, we report that in addition to mitophagy, Parkin mediates proteasome-dependent degradation of outer membrane proteins such as Tom20, Tom40, Tom70, and Omp25 of depolarized mitochondria. By contrast, degradation of the inner membrane and matrix proteins largely depends on mitophagy. Furthermore, Parkin induces rupture of the outer membrane of depolarized mitochondria, which also depends on proteasomal activity. Upon induction of mitochondrial depolarization, proteasomes are recruited to mitochondria in the perinuclear region. Neither proteasome-dependent degradation of outer membrane proteins nor outer membrane rupture is required for mitophagy. These results suggest that Parkin regulates degradation of outer and inner mitochondrial membrane proteins differently through proteasome-and mitophagydependent pathways.Parkinson disease is a progressive neurodegenerative disease that is characterized by postural changes, resting tremor, muscle rigidity, and weakness (1, 2). These symptoms are mainly caused by loss of dopaminergic neurons in the substantia nigra, and mitochondrial dysfunction appears to be the primary pathogenic event. Indeed, many of the products of Parkinson disease-related genes such as ␣-synuclein/PARK1/4, PARKIN/ PARK2, PINK1/PARK6, DJ-I/PARK7, and OMI/HTRA2 are physically and functionally linked to mitochondria (3,4).Parkin is a RING domain-containing E3 ubiquitin ligase, and its mutation causes autosomal recessive juvenile Parkinson disease (5). Recent studies have revealed that Parkin is important for mitochondrial quality control through degradation of damaged mitochondria. Narendra et al. (6) first demonstrated that Parkin translocates from the cytosol to depolarized mitochondria and triggers elimination of these mitochondria by autophagy, which is known as mitophagy. Targeting of Parkin to mitochondria requires PTEN-induced putative kinase 1 (Pink1), 3 another Parkinson disease-associated gene product (7-14). Pink1 is an extremely unstable mitochondrial protein, but it is stabilized upon mitochondrial depolarization and subsequently recruits Parkin.Autophagy is a membrane-mediated intracellular degradation process. A portion of cytoplasm is first enclosed by the double-membraned autophagosome, and the autophagosome then fuses with a lysosome to degrade the enclosed materials. Although autophagy has been thought to be mainly non-selective, recent studies have revealed that the autophagosomal membrane can recognize some specific proteins and organelles. Parkin-mediated autophagy of damaged mitochondria is one of the best examples of selective autophagy. However, the precise role of Parkin in the induction of mitophagy has not been fully elucidated. To date, several mitochondrial proteins, voltage-dependent anion channel 1 (VDAC1) (8), mitofusin (a mitochondrial pro-fusion factor)...

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Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients

Cited by 115 publications

References 44 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

Cytosolic cleaved PINK 1 represses P arkin translocation to mitochondria and mitophagy

Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane

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