The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance

Bertolin, Giulia; Ferrando-Miguel, Rosa; Jacoupy, Maxime; Traver, Sabine; Grenier, Karl; Greene, Andrew W; Dauphin, Aurélien; Waharte, François; Bayot, Aurélien; Salamero, Jean; Lombès, Anne; Bulteau, Anne‐Laure; Fon, Edward A.; Brice, Alexis; Corti, Olga

doi:10.4161/auto.25884

Cited by 119 publications

(116 citation statements)

References 44 publications

(89 reference statements)

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“…Parkin is recruited to mitochondria with preserved ΔΨm by PINK1, particularly when mitochondrial import is blocked. 22,39,40 PINK1 accumulated on mitochondria in cells overproducing HSD17B10, indicating that mitochondrial import mechanisms were overwhelmed (Supplementary Figure S2f). However, LC3-positive autophagic vesicles and immunoreactivity to the autophagic adaptor SQSTM1/p62 were rarely associated with mitochondrial clusters in cells coproducing HSD17B10 and Parkin, indicating an absence of mitophagy in these cells (Supplementary Figure S3).…”

Section: Hsd17b10mentioning

confidence: 99%

“…HSD17B10 is imported into mitochondria via the TOM complex, which is dedicated to the import of most nucleus-encoded mitochondrial proteins, 42 and Parkin and PINK1 associate with this complex. 21,22 We investigated whether these proteins interacted close to the TOM machinery. We used Förster resonance energy transfer (FRET) microscopy, involving the detection of changes in donor fluorescence intensities after photobleaching of the acceptor, with donor/acceptor protein pairs labeled with appropriate secondary antibodies, 22,43 to check for physical proximity (≤10 nm).…”

Section: Hsd17b10mentioning

confidence: 99%

“…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. 23 We report here the identification of a new mitochondrial Parkin substrate, the nucleus-encoded mitochondrial matrix 17-β hydroxysteroid dehydrogenase type 10 (HSD17B10), also known as endoplasmic reticulum-associated amyloidbeta-binding protein (ERAB), Aβ-binding alcohol dehydrogenase (ABAD) and 3-hydroxyacyl-CoA dehydrogenase type II (HADH2).…”

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confidence: 99%

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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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Section: Hsd17b10mentioning

confidence: 99%

Section: Hsd17b10mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…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: Discussionmentioning

confidence: 57%

“…c-Abl is localized in the nuclei and in the cytoplasm ( Figure S2) and a dual role in apoptosis has been proposed (26) in which nuclear c-Abl is pro-apoptotic whereas cytoplasmic c-Abl could actively inhibit apoptosis upon specific stimuli.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

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

Petit

Cartron

Oliver

et al. 2017

Cellular Signalling

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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

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Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

2021

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The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction in this fundamental cellular process is linked to a variety of pathologies including neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancer, demonstrating the importance of mitochondrial protein import machinery for cellular function. Correct import of proteins into mitochondria requires the co‐ordinated activity of multimeric protein translocation and sorting machineries located in both the outer and inner mitochondrial membranes, directing the imported proteins to the destined mitochondrial compartment. This dynamic process maintains cellular homeostasis, and its dysregulation significantly affects cellular signalling pathways and metabolism. This review summarises current knowledge of the mammalian mitochondrial import machinery and the pathological consequences of mutation of its components. In addition, we will discuss the role of mitochondrial import in cancer, and our current understanding of the role of mitochondrial import in neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease.

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The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance

Cited by 119 publications

References 44 publications

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

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

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

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

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