Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion

Simões, Tânia; Schuster, Ramona; Brave, Fabian den; Escobar-Henriques, Mafalda

doi:10.7554/elife.30015

Cited by 28 publications

(52 citation statements)

References 84 publications

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“…The DUBs USP15 and USP30 oppose parkin-mediated mitochondrial ubiquitination and mitophagy in cultured human cells. Interestingly, the yeast homologue of USP15 (Ubp12) deubiquitinates the MOM protein Fzo1, the yeast homologue of the mammalian parkin substrates mitofusin 1 and 2, pointing to a conserved role for USP15 in deubiquitination at the MOM ( Anton et al, 2013 ; SimoesSimões et al, 2018 ). Knockdown of the Drosophila homologs of USP15 ( CG8334 , hereafter called dUSP15 ) and USP30 ( CG3016 , hereafter dUSP30 ) largely rescues the mitochondrial defects of parkin-deficient fly muscle in vivo ( Bingol et al, 2014 ; Cornelissen et al, 2014 ).…”

Section: Resultsmentioning

confidence: 99%

Deficiency of parkin and PINK1 impairs age-dependent mitophagy in Drosophila

Cornelissen¹,

Vilain

Vints

et al. 2018

eLife

181

145

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Mutations in the genes for PINK1 and parkin cause Parkinson’s disease. PINK1 and parkin cooperate in the selective autophagic degradation of damaged mitochondria (mitophagy) in cultured cells. However, evidence for their role in mitophagy in vivo is still scarce. Here, we generated a Drosophila model expressing the mitophagy probe mt-Keima. Using live mt-Keima imaging and correlative light and electron microscopy (CLEM), we show that mitophagy occurs in muscle cells and dopaminergic neurons in vivo, even in the absence of exogenous mitochondrial toxins. Mitophagy increases with aging, and this age-dependent rise is abrogated by PINK1 or parkin deficiency. Knockdown of the Drosophila homologues of the deubiquitinases USP15 and, to a lesser extent, USP30, rescues mitophagy in the parkin-deficient flies. These data demonstrate a crucial role for parkin and PINK1 in age-dependent mitophagy in Drosophila in vivo.

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Section: Resultsmentioning

confidence: 99%

Deficiency of parkin and PINK1 impairs age-dependent mitophagy in Drosophila

Cornelissen¹,

Vilain

Vints

et al. 2018

eLife

181

145

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“…Recent studies in yeast showed that CDC48 proteins play a role in mitochondria fusion by regulating Fzo1 ubiquitylation and dynamics. Mutations in CDC48 cause mitochondria aggregation and fragmentation (Esaki and Ogura, 2012;Chowdhury et al, 2018;Simões et al, 2018). In addition, CDC48 is also involved in degradation of other mitochondrial outer membrane proteins such as Mdm34, Msp1, Tom70, and oxidation damaged mitochondrial proteins in yeast and Mcl1 in human (Xu et al, 2011;Hemion et al, 2014;Wu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

OPENER Is a Nuclear Envelope and Mitochondria Localized Protein Required for Cell Cycle Progression in Arabidopsis

2019

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Currently one-third of the proteins encoded by the Arabidopsis (Arabidopsis thaliana) genome are of unknown function. Some of these unknown proteins are likely to be involved in uncharacterized vital biological processes. Evolutionarily conserved single copy genes in flowering plants have been shown to be enriched in essential housekeeping functions. This together with publicly available gene expression data allows for a focused search for uncharacterized essential genes. Here we identify an essential single copy gene called OPENER (OPNR) in Arabidopsis. We show that OPNR is predominantly expressed in actively dividing cells and performs essential functions in seed development and root meristem maintenance. Cell cycle tracking using 5-ethynyl-2'-deoxyuridine staining and fluorescent cell cycle markers together with the increased size of nucleolus and nucleus in opnr mutants indicate that OPNR is required for cell cycle progression through the S or G2 phases. Intriguingly, OPNR localizes to the nuclear envelope and mitochondria. Furthermore, the nuclear envelope localization of OPNR is dependent on its interaction with nuclear inner membrane Sad1/UNC-84 (SUN) domain proteins SUN1 and SUN2. Taken together our results open a line of investigation into an evolutionarily conserved essential cellular process occurring in both the nuclear envelopes and mitochondria of dividing cells.

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“…Under non-stressed conditions Fzo1 and additional other OMM proteins are targeted by another Cdc48 complex involving Npl4, Ufd1, and Doa1, also called Ufd3 (Wu et al, 2016) (Figure 1 and Table 1). This might however reflect protein quality control triggered by experimental tagging of the membrane-bound proteins, since non-tagged endogenous Fzo1 is rather stabilized by Cdc48, which exerts a regulatory role during OMM fusion (Simões et al, 2018;Anton et al, 2019). Turnover of mitofusins by MAD is widely conserved among species including Marf in flies (Ziviani et al, 2010;Wang et al, 2016) and Mfn1/2 in mammals (Tanaka et al, 2010;Chan et al, 2011;Xu et al, 2011).…”

Section: Ups-dependent Turnover Of Mitochondrial Proteinsmentioning

confidence: 99%

Mitochondrial Quality Control Governed by Ubiquitin

Ravanelli

Brave

Hoppe

2020

Front. Cell Dev. Biol.

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Mitochondria are essential organelles important for energy production, proliferation, and cell death. Biogenesis, homeostasis, and degradation of this organelle are tightly controlled to match cellular needs and counteract chronic stress conditions. Despite providing their own DNA, the vast majority of mitochondrial proteins are encoded in the nucleus, synthesized by cytosolic ribosomes, and subsequently imported into different mitochondrial compartments. The integrity of the mitochondrial proteome is permanently challenged by defects in folding, transport, and turnover of mitochondrial proteins. Therefore, damaged proteins are constantly sequestered from the outer mitochondrial membrane and targeted for proteasomal degradation in the cytosol via mitochondrial-associated degradation (MAD). Recent studies identified specialized quality control mechanisms important to decrease mislocalized proteins, which affect the mitochondrial import machinery. Interestingly, central factors of these ubiquitindependent pathways are shared with the ER-associated degradation (ERAD) machinery, indicating close collaboration between both tubular organelles. Here, we summarize recently described cellular stress response mechanisms, which are triggered by defects in mitochondrial protein import and quality control. Moreover, we discuss how ubiquitindependent degradation is integrated with cytosolic stress responses, particularly focused on the crosstalk between MAD and ERAD.

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Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion

Cited by 28 publications

References 84 publications

Deficiency of parkin and PINK1 impairs age-dependent mitophagy in Drosophila

Deficiency of parkin and PINK1 impairs age-dependent mitophagy in Drosophila

OPENER Is a Nuclear Envelope and Mitochondria Localized Protein Required for Cell Cycle Progression in Arabidopsis

Mitochondrial Quality Control Governed by Ubiquitin

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