Regulation of ER-mitochondria contacts by Parkin via Mfn2

Basso, Valentina; Marchesan, Elena; Peggion, Caterina; Chakraborty, J.; Stockum, Sophia von; Giacomello, Marta; Ottolini, Denis; Debattisti, Valentina; Caicci, Federico; Tasca, Elisabetta; Pegoraro, Valentina; Angelini, C.; Antonini, Angelo; Bertoli, Alessandro; Brini, Marisa; Ziviani, Elena

doi:10.1016/j.phrs.2018.09.006

Cited by 168 publications

(164 citation statements)

References 76 publications

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“…4d,e). VDAC and Mfn2 have both been reported to be ubiquitinated by Parkin during mitophagy, yet neither were affected by bortezomib or bafilomycin under the basal conditions of this experiment (32,40). These data suggest that Parkin-mediated lysosomal degradation of Mff is independent of mitophagy.…”

Section: Parkin Mediates Lysosomal Degradation Of Mff Independent Of mentioning

confidence: 51%

“…These data suggest that Parkin-mediated lysosomal degradation of Mff is independent of mitophagy. large-scale mitophagy (32,40,41). The degradation of Mff by Parkin under basal conditions, together with its inactivity toward other known substrates under the same conditions, suggest that Parkin-mediated degradation of Mff is a regulatory mechanism independent of mitophagy.…”

Section: Parkin Mediates Lysosomal Degradation Of Mff Independent Of mentioning

confidence: 99%

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Parkin-mediated ubiquitination contributes to the constitutive turnover of mitochondrial fission factor (Mff)

Henley

Lee

Wilkinson

et al. 2019

Preprint

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The mitochondrial outer membrane protein Mitochondrial Fission Factor (Mff) plays a key role in both physiological and pathological fission. It is well established that in stressed or functionally impaired mitochondria the PINK1 recruits the ubiquitin ligase Parkin which ubiquitinates Mff to facilitate the removal of defective mitochondria and maintain the integrity mitochondrial network. Here we show that, in addition to this clearance pathway, Parkin also ubiquitinates Mff in a PINK1-dependent manner under basal, non-stressed conditions to regulate constitutive Mff turnover. We further show that removing Parkin with shRNA knockdown does not completely prevent Mff ubiquitination under these conditions indicating that at least one other ubiquitin ligase contributes to Mff proteostasis. These data demonstrate that Parkin plays a role in physiological maintenance of mitochondrial membrane protein composition in healthy mitochondria through constitutive low-level activation.

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Section: Parkin Mediates Lysosomal Degradation Of Mff Independent Of mentioning

confidence: 51%

Section: Parkin Mediates Lysosomal Degradation Of Mff Independent Of mentioning

confidence: 99%

Parkin-mediated ubiquitination contributes to the constitutive turnover of mitochondrial fission factor (Mff)

Henley

Lee

Wilkinson

et al. 2019

Preprint

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“…Miro1 is a crucial sensor for cytosolic calcium levels and is furthermore involved in the regulation of calcium homeostasis at the contact sites between mitochondria and the ER. MERCs are an emerging topic in the field of PD research and a number of PD-associated proteins were found to be involved in the regulation of MERCs, i.e., PINK1, Parkin, and LRRK2 [5][6][7]36]. Already in 2011, Kornmann and colleagues showed that Miro1 plays a role at the contact sites in mammalian Cos-7 cells [37].…”

Section: Discussionmentioning

confidence: 99%

“…PINK1, Parkin, LRRK2 and α-synuclein (α-syn) were recently found to be involved in the regulation of MERCs. Impaired function of these proteins caused fragmentation of the mitochondrial network, mitochondrial calcium dyshomeostasis and alterations of the amount of MERCs [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Variants in Miro1 Cause Alterations of ER-Mitochondria Contact Sites in Fibroblasts from Parkinson’s Disease Patients

Berenguer-Escuder

Großmann

Massart

et al. 2019

JCM

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Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD-associated proteins are involved in mitochondrial quality control, e.g., PINK1, Parkin, and LRRK2, which were recently identified as regulators of mitochondrial-endoplasmic reticulum (ER) contact sites (MERCs) linking mitochondrial homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly recognized to play a role in PD pathology. Recently, we identified the first PD patients carrying mutations in RHOT1, the gene coding for Miro1. Here, we describe two novel RHOT1 mutations identified in two PD patients and the characterization of the cellular phenotypes. Methods: Using whole exome sequencing we identified two PD patients carrying heterozygous mutations leading to the amino acid exchanges T351A and T610A in Miro1. We analyzed calcium homeostasis and MERCs in detail by live cell imaging and immunocytochemistry in patient-derived fibroblasts. Results: We show that fibroblasts expressing mutant T351A or T610A Miro1 display impaired calcium homeostasis and a reduced amount of MERCs. All fibroblast lines from patients with pathogenic variants in Miro1, revealed alterations of the structure of MERCs. Conclusion: Our data suggest that Miro1 is important for the regulation of the structure and function of MERCs. Moreover, our study supports the role of MERCs in the pathogenesis of PD and further establishes variants in RHOT1 as rare genetic risk factors for neurodegeneration.

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“…Several studies found that XBP1s increases expression of PGC1α (Arensdorf et al, 2013;Cheang et al, 2017). Interestingly, PGC1α activates the PINK1/Parkin mitophagy pathway, which is involved in ubiquitination of Mfn2 (Chen and Dorn, 2013;Basso et al, 2018;McLelland et al, 2018). Similarly, a growing list of miRNA has been implicated in the downregulation of Mfn2 but it is not clear if they are expressed in hASM and whether XBP1 is involved in their regulation (Kuhn et al, 2010;Dileepan et al, 2016;Purohit et al, 2019).…”

Section: Mfn2 and Er Stress Responsementioning

confidence: 99%

Endoplasmic Reticulum Stress and Mitochondrial Function in Airway Smooth Muscle

Delmotte

Sieck

2020

Front. Cell Dev. Biol.

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Inflammatory airway diseases such as asthma affect more than 300 million people worldwide. Inflammation triggers pathophysiology via such as tumor necrosis factor α (TNFα) and interleukins (e.g., IL-13). Hypercontraction of airway smooth muscle (ASM) and ASM cell proliferation are major contributors to the exaggerated airway narrowing that occurs during agonist stimulation. An emergent theme in this context is the role of inflammationinduced endoplasmic reticulum (ER) stress and altered mitochondrial function including an increase in the formation of reactive oxygen species (ROS). This may establish a vicious cycle as excess ROS generation leads to further ER stress. Yet, it is unclear whether inflammation-induced ROS is the major mechanism leading to ER stress or the consequence of ER stress. In various diseases, inflammation leads to an increase in mitochondrial fission (fragmentation), associated with reduced levels of mitochondrial fusion proteins, such as mitofusin 2 (Mfn2). Mitochondrial fragmentation may be a homeostatic response since it is generally coupled with mitochondrial biogenesis and mitochondrial volume density thereby reducing demand on individual mitochondrion. ER stress is triggered by the accumulation of unfolded proteins, which induces a homeostatic response to alter protein balance via effects on protein synthesis and degradation. In addition, the ER stress response promotes protein folding via increased expression of molecular chaperone proteins. Reduced Mfn2 and altered mitochondrial dynamics may not only be downstream to ER stress but also upstream such that a reduction in Mfn2 triggers further ER stress. In this review, we summarize the current understanding of the link between inflammation-induced ER stress and mitochondrial function and the role played in the pathophysiology of inflammatory airway diseases.

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Regulation of ER-mitochondria contacts by Parkin via Mfn2

Cited by 168 publications

References 76 publications

Parkin-mediated ubiquitination contributes to the constitutive turnover of mitochondrial fission factor (Mff)

Parkin-mediated ubiquitination contributes to the constitutive turnover of mitochondrial fission factor (Mff)

Variants in Miro1 Cause Alterations of ER-Mitochondria Contact Sites in Fibroblasts from Parkinson’s Disease Patients

Endoplasmic Reticulum Stress and Mitochondrial Function in Airway Smooth Muscle

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