A Stress-Responsive System for Mitochondrial Protein Degradation

Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Molecular cell (Impact Factor: 14.02). 11/2010; 40(3):465-80. DOI: 10.1016/j.molcel.2010.10.021
Source: PubMed


We show that Ydr049 (renamed VCP/Cdc48-associated mitochondrial stress-responsive--Vms1), a member of an unstudied pan-eukaryotic protein family, translocates from the cytosol to mitochondria upon mitochondrial stress. Cells lacking Vms1 show progressive mitochondrial failure, hypersensitivity to oxidative stress, and decreased chronological life span. Both yeast and mammalian Vms1 stably interact with Cdc48/VCP/p97, a component of the ubiquitin/proteasome system with a well-defined role in endoplasmic reticulum-associated protein degradation (ERAD), wherein misfolded ER proteins are degraded in the cytosol. We show that oxidative stress triggers mitochondrial localization of Cdc48 and this is dependent on Vms1. When this system is impaired by mutation of Vms1, ubiquitin-dependent mitochondrial protein degradation, mitochondrial respiratory function, and cell viability are compromised. We demonstrate that Vms1 is a required component of an evolutionarily conserved system for mitochondrial protein degradation, which is necessary to maintain mitochondrial, cellular, and organismal viability.

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    • "In addition, Ndfip1 has been reported to enhance MAVS degradation mediated by Smurf-1, which is another member of the HECT E3 ligase family (Wang et al, 2012). p97 (also known as VCP/CDC48) is a member of the type II AAA (ATPase associated with various activities) ATPase family and has been found to participate in a wide range of independent cellular processes including ER-and mitochondria-associated degradation (Ye et al, 2001; Jarosch et al, 2002; Rabinovich et al, 2002; Heo et al, 2010; Tanaka et al, 2010; Xu et al, 2011), autophagy (Ju et al, 2009; Vesa et al, 2009; Krick et al, 2010; Tresse et al, 2010), membrane reassembly (Latterich et al, 1995; Kondo et al, 1997; Hetzer et al, 2001; Ramadan et al, 2007), protein aggregation (Higashiyama et al, 2002; Yamanaka et al, 2004; Kobayashi et al, 2007; Song et al, 2007; Nishikori et al, 2008), DNA repair (Partridge et al, 2003; Indig et al, 2004), cell cycle progression (Cao et al, 2003; Fu et al, 2003; Ramadan et al, 2007; Mouysset et al, 2008), sex determination (Sasagawa et al, 2009), and neutralization of virus (Hauler et al, 2012). Many studies have shown that p97 is recruited, with the help of cofactors including Npl4, Ufd1, p47, UBXD7, and FAF1, to ubiquitinated substrates (Kondo et al, 1997; Ye et al, 2001; Song et al, 2005; Alexandru et al, 2008; Meyer et al, 2012; Yamanaka et al, 2012)—and through its segregase activity, p97 extracts its target proteins from their cellular environments mostly for proteasomal degradation. "
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    ABSTRACT: RIG-I is a well-studied sensor of viral RNA that plays a key role in innate immunity. p97 regulates a variety of cellular events such as protein quality control, membrane reassembly, DNA repair, and the cell cycle. Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181. Viral infection significantly strengthens the interaction between RIG-I and the p97 complex by a conformational change of RIG-I that exposes the CARDs and through K63-linked ubiquitination of these CARDs. Disruption of the p97 complex enhances RIG-I antiviral signaling. Consistently, administration of compounds targeting p97 ATPase activity was shown to inhibit viral replication and protect mice from vesicular stomatitis virus (VSV) infection. Overall, our study uncovered a previously unrecognized role for the p97 complex in protein ubiquitination and revealed the p97 complex as a potential drug target in antiviral therapy.
    The EMBO Journal 10/2015; DOI:10.15252/embj.201591888 · 10.43 Impact Factor
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    • "Accumulating lines of evidence also indicate that the ubiquitin-proteasome system is critical for regulation of mitochondrial quality control [117, 118]. Inhibition of this system results in the accumulation of damaged and dysfunctional mitochondria [119]. In addition, defects of the ubiquitin-proteasome system result in cardiac hypertrophy and dysfunction and defective cardiac responses to stress [120, 121]. "
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    ABSTRACT: The heart is highly sensitive to the aging process. In the elderly, the heart tends to become hypertrophic and fibrotic. Stiffness increases with ensuing systolic and diastolic dysfunction. Aging also affects the cardiac response to stress. At the molecular level, the aging process is associated with accumulation of damaged proteins and organelles, partially due to defects in protein quality control systems. The accumulation of dysfunctional and abnormal mitochondria is an important pathophysiological feature of the aging process, which is associated with excessive production of reactive oxygen species. Mitochondrial fusion and fission and mitochondrial autophagy are crucial mechanisms for maintaining mitochondrial function and preserving energy production. In particular, mitochondrial fission allows for selective segregation of damaged mitochondria, which are afterward eliminated by autophagy. Unfortunately, recent evidence indicates that mitochondrial dynamics and autophagy are progressively impaired over time, contributing to the aging process. This suggests that restoration of these mechanisms could delay organ senescence and prevent age-associated cardiac diseases. Here, we discuss the current understanding of the close relationship between mitochondrial dynamics, mitophagy, oxidative stress, and aging, with a particular focus on the heart.
    Oxidative medicine and cellular longevity 07/2014; 2014:210934. DOI:10.1155/2014/210934 · 3.36 Impact Factor
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    • "The diverse cellular functions are directed by various cofactors and/or adaptors that bind to either or both the N-terminal and the C-terminal regulatory regions of Cdc48p (Meyer et al., 2000; Madsen et al., 2009). It has recently been shown that Cdc48p is also involved in degradation of proteins of the mitochondrial outer membrane (MOM), such as Mcl1, an anti-apoptotic protein of the Bcl2 family, and Fzo1p/mitofusin, which is required for mitochondrial tethering before mitochondrial fusion (Heo et al., 2010; Tanaka et al., 2010; Xu et al., 2011; Esaki and Ogura, 2012). In particular, mutations that inhibit ATP hydrolysis by the D2 domain of Cdc48p (Cdc48p E588Q mutant) or eliminate the positive cooperativity of the D2 ATPase activity (Cdc48p E315Q mutant) affect the turnover of proteins involved in the mitochondrial fusion events, and thereby induced aggregation of the mitochondria (Esaki and Ogura, 2012). "
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    ABSTRACT: Cdc48p is a highly conserved cytosolic AAA chaperone that is involved in a wide range of cellular processes. It consists of two ATPase domains (D1 and D2), with regulatory regions at the N- and C-terminals. We have recently shown that Cdc48p regulates mitochondrial morphology, in that a loss of the ATPase activity or positive cooperativity in the D2 domain leads to severe fragmentations and aggregations of mitochondria in the cytoplasm. We have now used serial block-face scanning electron microscopy (SBF-SEM), an advanced three-dimensional (3D) electron microscopic technique to examine the structures and morphological changes of mitochondria in the yeast Saccharomyces cerevisiae We found that mutants lacking ATPase activity of Cdc48p showed mitochondrial fragmentations and aggregations, without fusion of the outer membrane. This suggests that the ATPase activity of Cdc48p is necessary for fusion of the outer membranes of mitochondria. Our results also show that SBF-SEM has considerable advantages in morphological and quantitative studies on organelles and intracellular structures in entire cells.
    Journal of Structural Biology 05/2014; 187(2). DOI:10.1016/j.jsb.2014.05.010 · 3.23 Impact Factor
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