Dual role of a GTPase conformational switch for membrane fusion by mitofusin ubiquitylation

Schuster, Ramona; Anton, Vincent; Simões, Tânia; Altin, Selver; Brave, Fabian den; Hermanns, Thomas; Hospenthal, Manuela K.; Komander, David; Dittmar, Gunnar; Dohmen, R. Jürgen; Escobar-Henriques, Mafalda

doi:10.26508/lsa.201900476

Cited by 13 publications

(26 citation statements)

References 80 publications

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“…Interestingly, these regions map to mutations associated with CMT2A [204], suggesting pathogenic relevance. Their importance as a driving force for membrane merging could be confirmed with subsequent functional analysis, allowing further dissection of the fusion mechanism [75,76,194,195,[205][206][207][208][209][210][211][212]. Consistent with the self-assembly properties of DRPs, mitofusins can be found in multiple oligomerization states [184,207] (Figure 4C).…”

Section: Mechanism Governing Omm Fusionmentioning

confidence: 61%

“…Other than its role in stress-induced MAD of mitofusins, Cdc48/p97 regulates mitochondrial dynamics by stimulating the activity of Fzo1, thus activating mitochondrial fusion [68,72,[74][75][76]132,133,182]. Generally, mitochondrial dynamics is mediated by large dynamin-like GTPase proteins (DRPs), a protein class whose function relies on self-oligomerization, coordinating GTP binding and hydrolysis with conformational changes [68,[183][184][185][186].…”

Section: Beyond Mad: Regulation Of the Mitofusins' Fusion Activity Bymentioning

confidence: 99%

“…This mitofusin isoform-specific region (MISR) was proposed to facilitate oligomerization via conformational changes in hinge 1. Finally, remodeling of the G-G interface allows several structural rearrangements [76,199,200].…”

Section: Mechanism Governing Omm Fusionmentioning

confidence: 99%

“…Fzo1 ubiquitylation occurs at a late step in the fusion process, after trans oligomerization and GTP hydrolysis [214]. Deletion of the ligase SCF Mdm30 [214,[224][225][226]230] or elimination of the lysines in Fzo1 required for its ubiquitylation [74,76,195,205] impairs fusion, leading to mitochondrial aggregation. These results defined that ubiquitylation is required for creating fusion-competent forms of Fzo1.…”

Section: Roles Of Ubiquitin and Cdc48 In Omm Fusionmentioning

confidence: 99%

“…Under stress conditions, Cdc48/p97 extracts ubiquitylated mitofusin from OMM and hands it over for proteasomal degradation, which inhibits mitochondrial fusion and also regulates contact sites between mitochondria and the ER [68,73]. In contrast to MAD, Cdc48/p97 also stabilizes the yeast mitofusin Fzo1 and promotes mitochondrial fusion, e.g., by segregating Fzo1 clusters at fusion sites, thereby recycling it for a new fusion event [74][75][76]. In mammalian cells, further examples of p97-dependent MAD have been proposed, highlighting the complexity of the regulation of mitochondrial dynamics by Cdc48/p97.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion

Escobar-Henriques

Anton

2020

IJMS

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Cdc48/p97 is a ring-shaped, ATP-driven hexameric motor, essential for cellular viability. It specifically unfolds and extracts ubiquitylated proteins from membranes or protein complexes, mostly targeting them for proteolytic degradation by the proteasome. Cdc48/p97 is involved in a multitude of cellular processes, reaching from cell cycle regulation to signal transduction, also participating in growth or death decisions. The role of Cdc48/p97 in endoplasmic reticulum-associated degradation (ERAD), where it extracts proteins targeted for degradation from the ER membrane, has been extensively described. Here, we present the roles of Cdc48/p97 in mitochondrial regulation. We discuss mitochondrial quality control surveillance by Cdc48/p97 in mitochondrial-associated degradation (MAD), highlighting the potential pathologic significance thereof. Furthermore, we present the current knowledge of how Cdc48/p97 regulates mitofusin activity in outer membrane fusion and how this may impact on neurodegeneration.

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Section: Mechanism Governing Omm Fusionmentioning

confidence: 61%

Section: Beyond Mad: Regulation Of the Mitofusins' Fusion Activity Bymentioning

confidence: 99%

Section: Mechanism Governing Omm Fusionmentioning

confidence: 99%

Section: Roles Of Ubiquitin and Cdc48 In Omm Fusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion

Escobar-Henriques

Anton

2020

IJMS

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Infectious viruses and neurodegenerative diseases: The mitochondrial defect hypothesis

Jiang,

Zhu,

Kang

et al. 2024

Reviews in Medical Virology

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Global attention is riveted on neurodegenerative diseases due to their unresolved aetiologies and lack of efficacious therapies. Two key factors implicated include mitochondrial impairment and microglial ageing. Several viral infections, including Herpes simplex virus‐1 (HSV‐1), human immunodeficiency virus (HIV) and Epstein‐Barr virus, are linked to heightened risk of these disorders. Surprisingly, numerous studies indicate viruses induce these aforementioned precipitating events. Epstein‐Barr virus, Hepatitis C Virus, HIV, respiratory syncytial virus, HSV‐1, Japanese Encephalitis Virus, Zika virus and Enterovirus 71 specifically impact mitochondrial function, leading to mitochondrial malfunction. These vital organelles govern various cell activities and, under specific circumstances, trigger microglial ageing. This article explores the role of viral infections in elucidating the pathogenesis of neurodegenerative ailments. Various viruses instigate microglial ageing via mitochondrial destruction, causing senescent microglia to exhibit activated behaviour, thereby inducing neuroinflammation and contributing to neurodegeneration.

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Docking and stability defects in mitofusin highlight the proteasome as a potential therapeutic target

et al. 2023

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Dual role of a GTPase conformational switch for membrane fusion by mitofusin ubiquitylation

Abstract: Mitochondrial fusion requires a conformational change in α4 of the GTPase domain, followed by AAA-ATPase regulation, thus revealing striking mechanistic similarities between small and large GTPases.

Cited by 13 publications

References 80 publications

Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion

Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion

Infectious viruses and neurodegenerative diseases: The mitochondrial defect hypothesis

Docking and stability defects in mitofusin highlight the proteasome as a potential therapeutic target

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