Hexokinase activity is required for recruitment of parkin to depolarized mitochondria

McCoy, Melissa K.; Kaganovich, Alice; Rudenko, Iakov N.; Ding, Jinhui; Cookson, Mark

doi:10.1093/hmg/ddt407

Cited by 80 publications

(92 citation statements)

References 48 publications

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“…UBE2A, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2D4, UBE2L3, UBE2N, UBE2R1 (also known as CDC34), UBE2S and UBE2T]. Similar to recent studies (Hasson et al, 2013;Lefebvre et al, 2013;McCoy et al, 2014), we have established a High Content Imaging (HCI) assay that allows unbiased monitoring of PINK1-dependent Parkin recruitment from the cytosol onto chemically de-energized mitochondria. Using HeLa cells that stably expressed an enhanced green fluorescent protein (EGFP)-fusion, the distribution of Parkin within cells was quantified as a ratio of the intensity of cytoplasmic and nuclear GFP (Cyto:Nuc) (Fig.…”

Section: Identification Of E2 Enzymes That Regulate Activation and MImentioning

confidence: 87%

Select E2 enzymes differentially regulate parkin activation and mitophagy

Fiesel

Moussaud-Lamodière

Ando

et al. 2014

Journal of Cell Science

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Loss-of-function mutations in the genes encoding PINK1 and Parkin (also known as PARK2) are the most common causes of recessive Parkinson's disease. Both together mediate the selective degradation of mitochondrial proteins and whole organelles via the proteasome and the autophagy-lysosome pathway (mitophagy). The mitochondrial kinase PINK1 activates and recruits the E3 ubiquitin ligase Parkin to de-energized mitochondria. However, the cognate E2 co-enzymes of Parkin in this ubiquitin-dependent pathway have not been investigated. Here, we discovered a total of four E2s that either positively or negatively regulate the activation, translocation and enzymatic functions of Parkin during mitochondrial quality control. UBE2D family members and UBE2L3 redundantly charged the RING-HECT hybrid ligase Parkin with ubiquitin, resulting in its initial activation and translocation to mitochondria. UBE2N, however, primarily operated through a different mechanism in order to mediate the proper clustering of mitochondria, a prerequisite for degradation. Strikingly, in contrast to UBE2D, UBE2L3 and UBE2N, depletion of UBE2R1 resulted in enhanced Parkin translocation and clustering upon mitochondrial uncoupling. Our study uncovered redundant, cooperative or antagonistic functions of distinct E2 enzymes in the regulation of Parkin and mitophagy that might suggest a putative role in Parkinson's disease pathogenesis.

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Section: Identification Of E2 Enzymes That Regulate Activation and MImentioning

confidence: 87%

Select E2 enzymes differentially regulate parkin activation and mitophagy

Fiesel

Moussaud-Lamodière

Ando

et al. 2014

Journal of Cell Science

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“…In sum, PINK1 can directly activate Akt via activation of mTORC2 to enhance cancer cell invasiveness [37] and promote cancer stem cell renewal via Notch signalling [50,98]. In HeLa cells, PINK1 induces Akt phosphorylation of hexokinase-II at the mitochondria, resulting in increased anaerobic glycolysis [99]. FOXO3a markedly induces human PINK1 transcription in cancer cells when PI3-kinase/Akt is inhibited and under stress conditions when growth factors and cytokines are withdrawn [35].…”

Section: Pink1 Function Overviewmentioning

confidence: 99%

PINK1 signalling in cancer biology

O’Flanagan¹,

O’Neill²

2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…1,[8][9][10][11][12] A series of mitochondrial targets interact with or are ubiquitylated by Parkin early in mitochondrial clearance. 9,[13][14][15][16][17][18][19] There is considerable interest in the possible direct role of some of these proteins in Parkin-dependent mitochondrial degradation, particularly for Mitofusin 1/2, 13,20 VDACs, 9,17 hexokinases 1/2 16,19 and subunits of the translocase of the OMM (TOM). 21,22 Moreover, the constitutive association of some Parkin with the OMM raises the question of a potential role of this protein in functions unrelated to mitophagy, such as regulating the degradation or targeting of specific mitochondrial proteins.…”

mentioning

confidence: 99%

Parkin maintains mitochondrial levels of the protective Parkinson’s disease-related enzyme 17-β hydroxysteroid dehydrogenase type 10

et al. 2015

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Mutations of the PARK2 and PINK1 genes, encoding the cytosolic E3 ubiquitin-protein ligase Parkin and the mitochondrial serine/ threonine kinase PINK1, respectively, cause autosomal recessive early-onset Parkinson's disease (PD). Parkin and PINK1 cooperate in a biochemical mitochondrial quality control pathway regulating mitochondrial morphology, dynamics and clearance. This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-β hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate. Parkin overproduction in cells increased mitochondrial HSD17B10 abundance by a mechanism involving ubiquitin chain extension, whereas PARK2 downregulation or deficiency caused mitochondrial HSD17B10 depletion in cells and mice. HSD17B10 levels were also found to be low in the brains of PD patients with PARK2 mutations. Confocal and Förster resonance energy transfer (FRET) microscopy revealed that HSD17B10 recruited Parkin to the translocase of the outer membrane (TOM), close to PINK1, both in functional mitochondria and after the collapse of mitochondrial membrane potential (ΔΨm). PD-causing PARK2 mutations impaired interaction with HSD17B10 and the HSD17B10-dependent mitochondrial translocation of Parkin. HSD17B10 overproduction promoted mitochondrial elongation and mitigated CCCP-induced mitochondrial degradation independently of enzymatic activity. These effects were abolished by overproduction of the fissionpromiting dynamin-related protein 1 (Drp1). By contrast, siRNA-mediated HSD17B10 silencing enhanced mitochondrial fission and mitophagy. These findings suggest that the maintenance of appropriate mitochondrial HSD17B10 levels is one of the mechanisms by which Parkin preserves mitochondrial quality. The loss of this protective mechanism may contribute to mitochondrial dysfunction and neuronal degeneration in autosomal recessive PD. Parkinson's disease (PD) is the most common neurodegenerative movement disorder. It is caused by progressive loss of the dopaminergic neurons of the substantia nigra pars compacta. It is mostly sporadic, but about 10% of cases are familial forms with Mendelian inheritance.1 Autosomal recessive forms of PD are caused by mutations of PARK2/parkin, PINK1, DJ-1 and ATP13A2. PARK2 mutations are responsible for almost 40% of cases beginning before the age of 45. Parkin is a cytosolic RING-in-between-RING ubiquitin ligase with HECT-like enzyme activity; 2 it has versatile ubiquitylation activities and various putative protein substrates with diverse functions, involved in different cellular processes.1 Genetic studies in Drosophila have shown Parkin and the mitochondrial serine/threonine kinase PINK1 to be components of a molecular pathway maintaining mitochondrial physiology. [3][4][5][6][7] In mammalian cells, PINK1 and Parkin cooperate in the clearance of dysfunctional mitochondria. The disruption of mitochondrial membrane (MM) potential (ΔΨm) by uncouplers or oxidative stress leads to PINK1 accumulation on the outer MM (OMM), the PINK1-dependent recruitment ...

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Hexokinase activity is required for recruitment of parkin to depolarized mitochondria

Cited by 80 publications

References 48 publications

Select E2 enzymes differentially regulate parkin activation and mitophagy

Select E2 enzymes differentially regulate parkin activation and mitophagy

PINK1 signalling in cancer biology

Parkin maintains mitochondrial levels of the protective Parkinson’s disease-related enzyme 17-β hydroxysteroid dehydrogenase type 10

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