A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics

Yonashiro, Ryo; Ishido, Satoshi; Kyo, Shinkou; Fukuda, Toshifumi; Gotō, Eiji; Matsuki, Yohei; Ohmura‐Hoshino, Mari; Sada, Kiyonao; Hotta, Hak; Yamamura, Hirohei; Inatome, Ryoko; Yanagi, Shigeru

doi:10.1038/sj.emboj.7601249

Cited by 341 publications

(371 citation statements)

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“…One possible target of the PINK1/ Parkin pathway is Drp1. It is currently unclear how Drp1 is recruited to mitochondria from the cytoplasm to promote the fission event (25), although Drp1 is subjected to multiple posttranslational modifications, including phosphorylation (45,46), SUMOylation (47)(48)(49), and ubiquitination (50,51), raising the possibility that one or more of these posttranslational modifications regulates the recruitment of Drp1 to mitochondria. Because Parkin can apparently promote both degradative and nondegradative forms of ubiquitination (52,53), the ubiquitination of Drp1 by Parkin could act in a nondegradative fashion to promote Drp1 to assemble with mitochondria to activate fission.…”

Section: Discussionmentioning

confidence: 99%

The PINK1/Parkin pathway regulates mitochondrial morphology

Poole

Thomas

Andrews

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

779

664

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Loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) or parkin genes, which encode a mitochondrially localized serine/ threonine kinase and a ubiquitin-protein ligase, respectively, result in recessive familial forms of Parkinsonism. Genetic studies in Drosophila indicate that PINK1 acts upstream of Parkin in a common pathway that influences mitochondrial integrity in a subset of tissues, including flight muscle and dopaminergic neurons. The mechanism by which PINK1 and Parkin influence mitochondrial integrity is currently unknown, although mutations in the PINK1 and parkin genes result in enlarged or swollen mitochondria, suggesting a possible regulatory role for the PINK1/Parkin pathway in mitochondrial morphology. To address this hypothesis, we examined the influence of genetic alterations affecting the machinery that governs mitochondrial morphology on the PINK1 and parkin mutant phenotypes. We report that heterozygous loss-offunction mutations of drp1, which encodes a key mitochondrial fission-promoting component, are largely lethal in a PINK1 or parkin mutant background. Conversely, the flight muscle degeneration and mitochondrial morphological alterations that result from mutations in PINK1 and parkin are strongly suppressed by increased drp1 gene dosage and by heterozygous loss-of-function mutations affecting the mitochondrial fusion-promoting factors OPA1 and Mfn2. Finally, we find that an eye phenotype associated with increased PINK1/Parkin pathway activity is suppressed by perturbations that reduce mitochondrial fission and enhanced by perturbations that reduce mitochondrial fusion. Our studies suggest that the PINK1/Parkin pathway promotes mitochondrial fission and that the loss of mitochondrial and tissue integrity in PINK1 and parkin mutants derives from reduced mitochondrial fission.caused by the degeneration of dopaminergic neurons in the midbrain. The molecular mechanisms underlying neurodegeneration in PD remain unclear, although substantial evidence suggests that mitochondrial dysfunction is a major contributor: Several mitochondrial toxins induce PD-like symptoms in humans and animal models (1, 2); systemic mitochondrial dysfunction appears to be a feature of a large proportion of PD sufferers (3); and several genes involved in rare heritable forms of Parkinsonism have been implicated in mitochondrial biology, including the PTEN-induced kinase 1 (PINK1) and parkin genes (4, 5).The PINK1 and parkin genes encode a mitochondrially localized serine/threonine kinase and an E3 ubiquitin-protein ligase, respectively (6-13). Although a number of substrates of PINK1 and Parkin have been described, these advances have led to dramatically varying models of pathogenesis (5,(14)(15)(16)(17)(18)(19), making it unclear precisely how PINK1 and Parkin influence neuronal integrity. Genetic studies of highly conserved Drosophila orthologs of parkin and PINK1 indicate that PINK1 acts upstream of Parkin in a common pathway that influences the integrity of flight muscle, sperm, and a subset of dopaminer...

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Section: Discussionmentioning

confidence: 99%

The PINK1/Parkin pathway regulates mitochondrial morphology

Poole

Thomas

Andrews

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

779

664

View full text Add to dashboard Cite

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“…the mitochondrial fission apparatus, DRP1 and FIS1, which are the human orthologues of yeast Dnm1p and Fis1p, respectively. However, there is a lack of consensus as to whether this ubiquitylation serves to target these factors for proteasomal degradation or facilitates other nonproteolytic functions (Nakamura et al, 2006;Yonashiro et al, 2006;Karbowski et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Analogous to ERAD, ubiquitin ligases intrinsic to the mitochondrial outer membrane, such as MARCHV/ MITOL (Nakamura et al, 2006;Yonashiro et al, 2006;Karbowski et al, 2007) and the newly described MULAN (Li et al, 2008), as well as E3s that are recruited to the mitochondrial outer membrane, such as the SCF, will be involved in this process. As with ERAD there is likely to be a high degree of complexity, and we predict that a number of mitochondrial and cytosolic proteins will be implicated in playing roles either in protecting proteins or facilitating their targeting to the UPS and in retro-translocation from mitochondrial membranes through as yet to be established mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin–Proteasome-dependent Degradation of a Mitofusin, a Critical Regulator of Mitochondrial Fusion

Cohen

Leboucher

Livnat-Levanon

et al. 2008

MBoC

151

169

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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 ubiquitinproteasome-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.

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“…(also known as MITOL), interacts with proteins for both fusion and fi ssion, including Mfn1, Mfn2, Drp1, and hFis1 [91][92][93] .…”

Section: Mitochondrial Involvement With Taumentioning

confidence: 99%

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

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The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau's functions in microtubule assembly and stabilization and with regard to its interactions with other proteins. We describe and analyze important post-translational modifications: hyperphosphorylation, ubiquitination, glycation, glycosylation, nitration, polyamination, proteolysis, acetylation, and methylation. We discuss how these post-translational modifi cations can alter tau's biological function. We analyze the role of mitochondrial health in neurodegeneration. We propose that microtubules could be a therapeutic target and review different approaches. Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and propose a mechanism of neurodegeneration.Keywords: tau; phosphorylation; neurodegeneration; tauopathies; mitochondria; microtubules; tubulin; kinases; phosphatases; Alzheimer's disease ·Review· IntroductionAlzheimer 's disease (AD), first described by Alois Alzheimer more than 100 years ago [1] , is a progressive neurodegenerative disorder, characterized by an insidious onset with irreversible cognitive declines that lead to profound mental deterioration causing dementia [2] . Two major forms of lesion characterize AD: amyloid as diffuse neurotic plaques primarily composed of the Aβ peptide [3] , which are mainly insoluble deposits of protein and cellular material, and neurofibrillary tangles composed of fi lamentous hyperphosphorylated tau protein that builds up inside the neuron [4,5] .Amyloid precursor protein (APP) is a highly conserved transmembrane protein [6] believed to play a role in synapse formation, synaptic plasticity, and neuronal survival [7][8][9] .In AD, APP is cleaved by β-and γ-secretases leading to the overproduction of an abnormal proteolytic byproduct called amyloid beta (Aβ) [10] . Upon cleavage fragments of Aβ of various sizes are released from the membrane and aggregate in the brain to form the characteristic plaques seen in AD. Plaques are composed primarily of the 40 and 42 amino-acid peptide fragments Aβ40 and Aβ42, the latter being the predominant species. In addition, Aβ42 is more prone to aggregation and deposition and therefore the cause of neurotoxicity, as well as synaptic loss [11] .The second lesion in AD is formed by aggregates of the microtubule-associated protein tau, which forms intracytoplasmic neuronal inclusions or neurofibrillary tangles when hyperphosphorylated [12] . Tau is associated with neurons of the central nervous system [13] and its main biological function is promoting the in vitro assembly and stabilization of microtubules in the cytoskeleton [14,15] . Tau is a phosphoprotein that is encoded by a single gene, MAPT, located on chromosome 17q21 [16] ; alternative splicing of the gene produces six major isoforms expressed in the adult human brain [17] . Isoforms derive their names from the number of microtubule-binding repeat s...

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A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics

Cited by 341 publications

References 38 publications

The PINK1/Parkin pathway regulates mitochondrial morphology

The PINK1/Parkin pathway regulates mitochondrial morphology

Ubiquitin–Proteasome-dependent Degradation of a Mitofusin, a Critical Regulator of Mitochondrial Fusion

Tau-induced neurodegeneration: mechanisms and targets

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