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

Im, Chang‐Nim; Lee, Jae‐Seon; Zheng, Ying; Seo, Jeong‐Sun

doi:10.1002/jcb.21064

Cited by 61 publications

(52 citation statements)

References 46 publications

(55 reference statements)

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“…overexpression were reported in hepatocytes and PC12 cells (Im et al, 2007;Liu et al, 2005), this is the first evidence, to the best of our knowledge, showing protection against loss of mitochondrial membrane potential and cellular ATP depletion by Hsp75 overexpression. Oxidative stress, mitochondrial dysfunction, and ATP depletion are interconnected during ischemia.…”

Section: Discussionmentioning

confidence: 78%

Overexpression of Mitochondrial Hsp70/Hsp75 Protects Astrocytes against Ischemic Injury in vitro

Voloboueva

Duan

Ouyang

et al. 2007

J Cereb Blood Flow Metab

107

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Mitochondrial heat shock protein 70 (mtHsp70/Hsp75/Grp75/mortalin/TRAP-1/PBP74) is an essential mitochondrial chaperone and a member of the heat shock protein 70 (HSP70) family. Although many studies have shown the protective properties of overexpression of the cytosolic inducible member of the HSP70 family, Hsp72, few studies have investigated the protective potential of Hsp75 against ischemic injury. Mitochondria are one of the primary targets of ischemic injury in astrocytes. In this study, we analyzed the effects of Hsp75 overexpression on cellular levels of reactive oxygen species (ROS), mitochondrial membrane potential, ATP levels, and viability during the ischemia-like conditions of oxygen-glucose deprivation (OGD) or glucose deprivation (GD) in primary astrocytic cultures. We show that Hsp75 overexpression decreases ROS production and preserves mitochondrial membrane potential during GD, and preserves ATP levels and cell viability during OGD. These findings indicate that Hsp75 can provide protection against ischemia-like in vitro injury and suggest that it should be further studied as a potential candidate for protection against ischemic injury.

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Section: Discussionmentioning

confidence: 78%

Overexpression of Mitochondrial Hsp70/Hsp75 Protects Astrocytes against Ischemic Injury in vitro

Voloboueva

Duan

Ouyang

et al. 2007

J Cereb Blood Flow Metab

107

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“…Much literature has demonstrated that TRAP1 plays an important role in inhibiting cell death caused by a reactive oxygen species (ROS) (23,24). Silencing TRAP1 through siRNA increases ROS accumulation, whereas TRAP1 over-expression decreases ROS production (25,26). Granzyme M, a serine protease capable of inducing apoptosis, can cleave TRAP1 to compromise the ATPase activity and abolish its antagonistic functions against ROSs, resulting in ROS accumulation and cell death (25).…”

Section: Trap1 Protects Mitochondria From Oxidative Stressesmentioning

confidence: 99%

TRAP1 regulation of mitochondrial life or death decision in cancer cells and mitochondria-targeted TRAP1 inhibitors

Kang¹

2012

BMB Reports

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“…Several studies have suggested that TRAP1 plays a cytoprotective role by buffering reactive oxygen species (ROS)-mediated oxidative stress (5,6), and others have reported that TRAP1 overexpression attenuates ROS production (7). The antioxidant properties of TRAP1, together with its reported ability to regulate opening of the mitochondrial permeability transition pore (8,9), may contribute to its antiapoptotic activity (4).…”

mentioning

confidence: 99%

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

Yoshida

Tsutsumi²,

Mühlebach

et al. 2013

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

228

272

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TRAP1 (TNF receptor-associated protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer molecular target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable. Some cancers express less TRAP1 than do their normal tissue counterparts, suggesting that TRAP1 function in mitochondria of normal and transformed cells is more complex than previously appreciated. We have used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1-deficiency promotes an increase in mitochondrial respiration and fatty acid oxidation, and in cellular accumulation of tricarboxylic acid cycle intermediates, ATP and reactive oxygen species. At the same time, glucose metabolism is suppressed. TRAP1-deficient cells also display strikingly enhanced invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. Taken together with the observation that TRAP1 expression is inversely correlated with tumor grade in several cancers, these data suggest that, in some settings, this mitochondrial molecular chaperone may act as a tumor suppressor.M olecular chaperones help to maintain cellular homeostasis.The heat-shock protein 90 (HSP90) family of molecular chaperones is highly conserved from bacteria to mammals. HSP90 itself is an essential molecular chaperone found in the cytoplasm and nucleus of all eukaryotic cells (1, 2). In multicellular eukaryotes, the HSP90 family includes the mitochondrial chaperone TRAP1 (TNF receptor-associated protein), which shares 50% sequence similarity with HSP90. Although TRAP1 binds and hydrolyzes ATP in an analogous manner to HSP90 (3), its cellular function is less well understood. Thus, although many HSP90-dependent proteins ("clients") and interacting cochaperones have been described (www.picard.ch/downloads/Hsp90interactors.pdf), the validated list of TRAP1-dependent clients is quite small and TRAP1-interacting cochaperones, if they exist, have yet to be identified (4).Several studies have suggested that TRAP1 plays a cytoprotective role by buffering reactive oxygen species (ROS)-mediated oxidative stress (5, 6), and others have reported that TRAP1 overexpression attenuates ROS production (7). The antioxidant properties of TRAP1, together with its reported ability to regulate opening of the mitochondrial permeability transition pore (8, 9), may contribute to its antiapoptotic activity (4). For these reasons, TRAP1 has been proposed as an anticancer molecular target, and first-generation inhibitors have shown some anticancer activity in preclinical models (10). However, these inhibitors do not distinguish between HSP90 and TRAP1 (11), and TRAP1 expression in cancer is variable but HSP90 comprises as much as 5% of...

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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

Cited by 61 publications

References 46 publications

Overexpression of Mitochondrial Hsp70/Hsp75 Protects Astrocytes against Ischemic Injury in vitro

Overexpression of Mitochondrial Hsp70/Hsp75 Protects Astrocytes against Ischemic Injury in vitro

TRAP1 regulation of mitochondrial life or death decision in cancer cells and mitochondria-targeted TRAP1 inhibitors

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

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