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Ubiquitin-proteasome-dependent degradation of a mitofusin, a critical regulator of mitochondrial fusion.

ABSTRACT: The mitochondrion is a dynamic membranous network whose morphology is conditioned by the equilibrium between ongoing fusion and fission of mitochondrial membranes. In the budding yeast, Saccharomyces cerevisiae, the transmembrane GTPase Fzo1p controls fusion of mitochondrial outer membranes. Deletion or overexpression of Fzo1p have both been shown to alter the mitochondrial fusion process indicating that maintenance of steady-state levels of Fzo1p are required for efficient mitochondrial fusion. Cellular levels of Fzo1p are regulated through degradation of Fzo1p by the F-box protein Mdm30p. How Mdm30p promotes degradation of Fzo1p is currently unknown. We have now determined that during vegetative growth Mdm30p mediates ubiquitylation of Fzo1p and that degradation of Fzo1p is an ubiquitin-proteasome-dependent process. In vivo, Mdm30p associates through its F-box motif with other core components of Skp1-Cullin-F-box (SCF) ubiquitin ligases. We show that the resulting SCF(Mdm30p) ligase promotes ubiquitylation of Fzo1p at mitochondria and its subsequent degradation by the 26S proteasome. These results provide the first demonstration that a cytosolic ubiquitin ligase targets a critical regulatory molecule at the mitochondrial outer membrane. This study provides a framework for developing an understanding of the function of Mdm30p-mediated Fzo1p degradation in the multistep process of mitochondrial fusion.

SUBMITTER: Cohen MM

PROVIDER: S-EPMC2397313 | biostudies-other | 2008 Jun

REPOSITORIES: biostudies-other

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Ubiquitin-proteasome-dependent degradation of a mitofusin, a critical regulator of mitochondrial fusion.

Cohen Mickael M J MM Leboucher Guillaume P GP Livnat-Levanon Nurit N Glickman Michael H MH Weissman Allan M AM

Molecular biology of the cell 20080319 6

The mitochondrion is a dynamic membranous network whose morphology is conditioned by the equilibrium between ongoing fusion and fission of mitochondrial membranes. In the budding yeast, Saccharomyces cerevisiae, the transmembrane GTPase Fzo1p controls fusion of mitochondrial outer membranes. Deletion or overexpression of Fzo1p have both been shown to alter the mitochondrial fusion process indicating that maintenance of steady-state levels of Fzo1p are required for efficient mitochondrial fusion. ...[more]

PMID: 18353967

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Project description:Although the neurobiological basis of autism spectrum disorder (ASD) is not fully understood, recent studies have indicated the potential role of GABAA receptors in the pathophysiology of ASD. GABAA receptors play a crucial role in various neurodevelopmental processes and adult neuroplasticity. However, the mechanism(s) of regulation of GABAA receptors in ASD remains poorly understood.Postmortem middle frontal gyrus tissues (13 ASD and 13 control subjects) were used. In vitro studies were performed in primary cortical neurons at days in vitro (DIV) 14. The protein levels were examined by western blotting. Immunofluorescence studies were employed for cellular localization. The gene expression was determined by RT-PCR array and qRT-PCR.A significant decrease in GABAA?1 protein, but not mRNA levels was found in the middle frontal gyrus of ASD subjects indicating a post-translational regulation of GABAA receptors in ASD. At the cellular level, treatment with proteasomal inhibitor, MG132, or lactacystin significantly increased GABAA?1 protein levels and Lys48-linked polyubiquitination of GABAA?1, but reduced proteasome activity in mouse primary cortical neurons (DIV 14 from E16 embryos). Moreover, treatment with betulinic acid, a proteasome activator significantly decreased GABAA?1 protein levels in cortical neurons indicating the role of polyubiquitination of GABAA?1 proteins with their subsequent proteasomal degradation in cortical neurons. Ubiquitination specific RT-PCR array followed by western blot analysis revealed a significant increase in SYVN1, an endoplasmic reticulum (ER)-associated degradation (ERAD) E3 ubiquitin ligase in the middle frontal gyrus of ASD subjects. In addition, the inhibition of proteasomal activity by MG132 increased the expression of GABAA?1 in the ER. The siRNA knockdown of SYVN1 significantly increased GABAA?1 protein levels in cortical neurons. Moreover, reduced association between SYVN1 and GABAA?1 was found in the middle frontal gyrus of ASD subjects.SYVN1 plays a critical role as an E3 ligase in the ubiquitin proteasome system (UPS)-mediated GABAA?1 degradation. Thus, inhibition of the ubiquitin-proteasome-mediated GABAA?1 degradation may be an important mechanism for preventing GABAA?1 turnover to maintain GABAA?1 levels and GABA signaling in ASD.

Dataset Information

Ubiquitin-proteasome-dependent degradation of a mitofusin, a critical regulator of mitochondrial fusion.

Publications

Ubiquitin-proteasome-dependent degradation of a mitofusin, a critical regulator of mitochondrial fusion.

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