Mitochondrial Dysfunction via Disruption of Complex II Activity during Iron Chelation—Induced Senescence-like Growth Arrest of Chang Cells

Yoon, Young-Sil; Cho, Hyeseong; Lee, Jae-Ho; Yoon, Gyesoon

doi:10.1007/978-3-662-41088-2_13

Cited by 6 publications

(9 citation statements)

References 18 publications

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“…6C) at 3 days p.i. The effect of altered activity of a respiratory chain complex on ⌬⌿ m and/or intracellular ATP content can occur with a time delay (45). Besides ATP consumption, RV could require mitochondria to obtain cardiolipin, a constituent of RV particles (1).…”

Section: Discussionmentioning

confidence: 99%

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Involvement of p32 and Microtubules in Alteration of Mitochondrial Functions by Rubella Virus

Claus

Chey

Sticht

et al. 2011

J Virol

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The interaction of the rubella virus (RV) capsid (C) protein and the mitochondrial p32 protein is believed to participate in virus replication. In this study, the physiological significance of the association of RV with mitochondria was investigated by silencing p32 through RNA interference. It was demonstrated that downregulation of p32 interferes with microtubule-directed redistribution of mitochondria in RV-infected cells. However, the association of the viral C protein with mitochondria was not affected. When cell lines either pretreated with respiratory chain inhibitors or cultivated under (mild) hypoxic conditions were infected with RV, viral replication was reduced in a time-dependent fashion. Additionally, RV infection induces increased activity of mitochondrial electron transport chain complex III, which was associated with an increase in the mitochondrial membrane potential. These effects are outstanding among the examples of mitochondrial alterations caused by viruses. In contrast to the preferential localization of p32 to the mitochondrial matrix in most cell lines, RV-permissive cell lines were characterized by an almost exclusive membrane association of p32. Conceivably, this contributes to p32 function(s) during RV replication. The data presented suggest that p32 fulfills an essential function for RV replication in directing trafficking of mitochondria near sites of viral replication to meet the energy demands of the virus.Rubella virus (RV), a single-stranded RNA virus, is the sole member of the genus Rubivirus in the family Togaviridae and causes a generally mild exanthematous childhood disease. However, severe malformations known as congenital rubella syndrome may result from the infection of seronegative women, especially during the first trimester of pregnancy. The mechanisms contributing to RV teratogenesis remain largely unknown. The 5Ј-proximal open reading frame (ORF) of the genome encodes the two replicase proteins P150 and P90, while the 3Ј ORF encodes the structural proteins, the capsid (C) protein and two envelope glycoproteins (E1 and E2). Viral RNA synthesis occurs on replication complexes, which are membrane bound to a structure called the cytopathic vacuole (CPV). CPVs are of endolysosomal origin and surrounded by rough endoplasmic reticulum (RER) cisternae, the Golgi apparatus, and mitochondria (13,14). CPVs are replication factories and provide a protected environment for virus replication and assembly.The C protein of RV represents one of the few RNA virusencoded structural proteins that interact with mitochondria and is so far the only known viral protein that impairs protein transport into mitochondria (17). Additionally, the C protein participates in viral RNA synthesis (42), which is emphasized by its accumulation around CPVs (14). The C protein is also involved in the process of mitochondrial redistribution to a perinuclear region in proximity to CPVs (3,28) and interacts with the p32 protein (3). Besides its predominant localization to the matrix of mitochondria, p32 is a...

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Section: Discussionmentioning

confidence: 99%

“…Primary antibodies were applied for 1.5 h at 37°C. Three washes with PBS were followed by incubation with a 1:100 dilution of the following secondary antibodies for 45 Statistical analysis. Student's t test was applied to determine statistical significance.…”

Section: Methodsmentioning

confidence: 99%

Involvement of p32 and Microtubules in Alteration of Mitochondrial Functions by Rubella Virus

Claus

Chey

Sticht

et al. 2011

J Virol

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“…As shown in Figure 6C, TRAP1 overexpression partially reduced DFO-induced ROS generation as compared with the EV-transfected cells (P < 0.05). SA-b-gal activity, known as a senescence-associated biomarker, was previously found to increase in DFO-treated Chang cells and other cells [Yoon et al, 2003[Yoon et al, , 2004. To determine the effect of TRAP1 on SAb-gal activity by DFO treatment, we conducted SA-b-gal staining in DFO-treated EV or TRAP1 cells.…”

Section: Trap1 Overexpression Reduces Dfo-mediatedmentioning

confidence: 99%

“…For example, DFO induces a series of changes such as G1 cell cycle arrest, a decrease in the levels of ATP, and a flattening of cellular morphology in a normal human hepatocyte cell line, Chang cells. These DFO-associated alterations have been attributed, at least in part, to mitochondrial defects such as inhibition of complex II activity through a down-regulation of iron-sulfur subunit [Yoon et al, 2003[Yoon et al, , 2004.…”

mentioning

confidence: 99%

Iron chelation study in a normal human hepatocyte cell line suggests that tumor necrosis factor receptor‐associated protein 1 (TRAP1) regulates production of reactive oxygen species

Lee

Zheng

et al. 2006

J of Cellular Biochemistry

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Iron is an essential component of many proteins, and has crucial roles in the proper functioning of proteins involved in cellular respiration, proliferation, and differentiation. It has been recently reported that the deferoxamine (DFO), an iron chelator, induces mitochondrial dysfunction, characterized by an attenuation of oxidative phosphorylation, as well as senescence-like cellular morphology. However, the effects of DFO on mitochondrial heat shock proteins (HSPs) remain poorly understood. In this study, we examined the effect of DFO on tumor necrosis factor receptor-associated protein 1 (TRAP1), a representative mitochondrial HSP, in a normal human hepatocyte cell line, Chang cells. DFO specifically decreased TRAP1 levels, increasing reactive oxygen species (ROS) and caveolin-1 (Cav-1), a marker protein of senescence. To examine whether these effects of DFO are reversed, we established TRAP1-overexpressing Chang cells. DFO treatment to TRAP1-overexpressing cells resulted in decreases in levels of ROS, Cav-1, glutathione peroxidase (GPX), and manganese superoxide dismutase (MnSOD) levels as well as senescence-associated beta-galactosidase (SA beta-gal) activity. These results suggest that TRAP1 might play a role in protecting mitochondria against damaging stimuli via decrease of ROS generation.

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“…10 This finding suggests that unnecessary reinforcement of mitochondrial morphogenesis may generate another senescent stress in the cell. These functional defects and morphogenic changes in the mitochondria have been commonly observed in diverse stress-induced senescence systems, including replicative senescence, 6,[10][11][12] implying their importance in the development of cell senescence.…”

Section: Functional and Morphogenic Alteration Of Mitochondria In Celmentioning

confidence: 99%

Roles of GSK3 in metabolic shift toward abnormal anabolism in cell senescence

Kim

Seo

Park³

et al. 2010

Annals of the New York Academy of Sciences

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Diverse metabolic alterations, including mitochondrial dysfunction, have often been reported as characteristic phenotypes of senescent cells. However, the overall consequence of senescent metabolic features, how they develop, and how they are linked to other senescent phenotypes, such as enlarged cell volume, increased granularity, and oxidative stress, is not clear. We investigated the potential roles of glycogen synthase kinase 3 (GSK3), a multifunctional kinase, in the development of the metabolic phenotypes in cell senescence. The inactivation of GSK3 via phosphorylation is commonly observed in diverse cell senescences. Furthermore, subcytotoxic concentration of GSK3 inhibitor was sufficient to induce cellular senescence, accompanied by augmented anabolism, such as enhanced protein synthesis, and increased glycogenesis and lipogenesis, in addition to mitochondrial dysfunction. Anabolism was accomplished through glycogen synthase, eIF2B, and SREBP1. These metabolic features seem to contribute to an increase in cellular mass by increasing glycogen granules, protein mass, and organelles. Taken together, our results suggest that GSK3 is one of the key modulators of metabolic alteration, leading the cells to senescence.

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Mitochondrial Dysfunction via Disruption of Complex II Activity during Iron Chelation—Induced Senescence-like Growth Arrest of Chang Cells

Cited by 6 publications

References 18 publications

Involvement of p32 and Microtubules in Alteration of Mitochondrial Functions by Rubella Virus

Involvement of p32 and Microtubules in Alteration of Mitochondrial Functions by Rubella Virus

Iron chelation study in a normal human hepatocyte cell line suggests that tumor necrosis factor receptor‐associated protein 1 (TRAP1) regulates production of reactive oxygen species

Roles of GSK3 in metabolic shift toward abnormal anabolism in cell senescence

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