Combined and Individual Mitochondrial HSP60 and HSP10 Expression in Cardiac Myocytes Protects Mitochondrial Function and Prevents Apoptotic Cell Deaths Induced by Simulated Ischemia-Reoxygenation

Lin, Keh Ming; Lin, Bryan; Lian, Ian; Mestril, Ruben; Scheffler, Immo E.; Dillmann, Wolfgang H.

doi:10.1161/01.cir.103.13.1787

Cited by 255 publications

(206 citation statements)

References 15 publications

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“…General protection at the mitochondrial level has been demonstrated in cardiac myocytes by Hsp60 (45). In the present study, steady-state accumulation of intracellular ␤-amyloid was not altered by the overexpression of Hsp60 in neuroblastoma cells, whereas moderate to slight reductions were observed after the overexpression of Hsp70 and Hsp90, respectively.…”

Section: Discussionsupporting

confidence: 48%

Differential Effects of Mitochondrial Heat Shock Protein 60 and Related Molecular Chaperones to Prevent Intracellular β-Amyloid-induced Inhibition of Complex IV and Limit Apoptosis

Veereshwarayya

Kumar

Rosen

et al. 2006

Journal of Biological Chemistry

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118

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Defects in mitochondrial oxidative metabolism, in particular decreased activity of cytochrome c oxidase, have been reported in Alzheimer disease tissue and in cultured cells that overexpress amyloid precursor protein. Mitochondrial dysfunction contributes to neurodegeneration in Alzheimer disease partly through formation of reactive oxygen species and the release of sequestered molecules that initiate programmed cell death pathways. The heat shock proteins (HSP) are cytoprotective against a number of stressors, including accumulations of misfolded proteins and reactive oxygen species. We reported on the property of Hsp70 to protect cultured neurons from cell death caused by intraneuronal ␤-amyloid. Here we demonstrate that Hsp60, Hsp70, and Hsp90 both alone and in combination provide differential protection against intracellular ␤-amyloid stress through the maintenance of mitochondrial oxidative phosphorylation and functionality of tricarboxylic acid cycle enzymes. Notably, ␤-amyloid was found to selectively inhibit complex IV activity, an effect selectively neutralized by Hsp60. The combined effect of HSPs was to reduce the free radical burden, preserve ATP generation, decrease cytochrome c release, and prevent caspase-9 activation, all important mediators of ␤-amyloid-induced neuronal dysfunction and death.Current evidence indicates that intracellular accumulation of ␤-amyloid in neurons leads to the formation of an insoluble pool in which the peptide is highly aggregated as well as a soluble pool in which toxic oligomers are found (1-3). A␤-(1-42) 2 is generated in both the endoplasmic reticulum and the intermediate compartment (4). Because neuronal mitochondria are frequently found in close association with the endoplasmic reticulum (5), it is possible that the local concentration of A␤ is relatively higher in their vicinity compared with other cellular locations. Conceivably, exposure of mitochondria to A␤ alters membrane stability and/or their normal oxidative phosphorylation functions. These considerations make it feasible that a direct impact of intracellular ␤-amyloid on mitochondrial function may contribute to neurodegeneration in AD through energy failure and activation of apoptosis.A recent study of mitochondrial function in a transgenic model and in AD patients has shown that oxidative phosphorylation is inhibited by the presence of intracellular ␤-amyloid (6), leading to a reduction in ATP production. ATP depletion leads to partial membrane depolarization, release of the voltagedependent Mg 2ϩ block of NMDA receptors, increase in calcium influx, and a decrease in calcium buffering capacity (7). The increase in intracellular calcium enhances free radical generation and triggers several pathways that lead to cellular dysfunction and death (8). Examination of brains from patients suffering from AD identifies a high fraction of cells undergoing apoptosis, which is suggested as an important mechanism for neuronal cell loss (9). One of the major events related to activation of the intrinsic programmed ce...

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Section: Discussionsupporting

confidence: 48%

Differential Effects of Mitochondrial Heat Shock Protein 60 and Related Molecular Chaperones to Prevent Intracellular β-Amyloid-induced Inhibition of Complex IV and Limit Apoptosis

Veereshwarayya

Kumar

Rosen

et al. 2006

Journal of Biological Chemistry

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118

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“…For example, the number of mitochondria in the cardiomyocytes substantially increases due to the great energy demands (Mayor and Cuezva, 1985). Thus, the high abundant existence of functional mitochondria in cardiomyocytes is essential in producing enough ATP required for normal cardiac contractile function (Lin et al, 2001). In addition, mitochondria participate in the maintaining of ion and reactive oxygen species (ROS) homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial network in the heart

Zhou

Gao

et al. 2012

Protein Cell

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Mitochondria are subcellular organelles that provide energy for the cell. They form a dynamic tubular network and play an important role in maintaining the cell function and integrity. Heart is a powerful organ that supplies the motivation for circulation, thereby requiring large amounts of energy. Thus, the healthiness of cardiomyocytes and mitochondria is necessary for the normal cardiac function. Mitochondria not only lie in the center of the cell apoptotic pathway, but also are the major source of reactive oxygen species (ROS) generation. Mitochondrial morphological change includes fission and fusion that are regulated by a large number of proteins. In this review we discuss the regulators of mitochondrial fission/fusion and their association with cell apoptosis, autophagy and ROS production in the heart.

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“…In complex with HSP10, it provides a secluded environment optimal for the unfolded or misfolded protein intermediates to return to their native conformation. Several experiments have implicated HSP60 in protecting cardiac myocytes during hypoxia possibly by complexing with Bax and preventing its translocation to the outer mitochondrial membrane (17,18). HSP60 also protects epithelial cells from stress-induced death through activation of extracellular signal-regulated kinase (ERK) and inhibition of caspase 3 (19).…”

mentioning

confidence: 99%

Cytosolic Accumulation of HSP60 during Apoptosis with or without Apparent Mitochondrial Release

Chandra

Choy

Tang³

2007

Journal of Biological Chemistry

215

121

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Most heat shock proteins (HSPs) have pro-survival functions. However, the role of HSP60, a mitochondrial matrix protein, is somewhat controversial with both pro-survival and pro-apoptotic functions reported. Here we show that in numerous apoptotic systems HSP60 protein accumulates in the cytosol. In BMD188-induced cell death, HSP60 accumulates in the cytosol with significant mitochondrial release. In contrast, in apoptosis induced by multiple other inducers, the cytosolic HSP60 accumulates without an apparent mitochondrial release. The short interfering RNA-mediated knockdown experiments revealed that in BMD188-induced apoptosis, HSP60 has a pro-death function and that the pro-death role of HSP60 seems to involve caspase-3 maturation and activation in the cytosol. In contrast, HSP60 appears to play a pro-survival role in other apoptotic systems where there is no apparent mitochondrial release as its knockdown promotes cell death. In these latter apoptotic systems HSP60 does not associate with active caspase-3. In both cases, HSP60 does not appreciably interact with Bax. Taken together, our results suggest the following: 1) cytosolic accumulation of HSP60 represents a common phenomenon during apoptosis induction; 2) cytosolic HSP60 accumulation during apoptosis occurs either with or without apparent mitochondrial release; and 3) the cytosolically accumulated HSP60 possesses either pro-survival or pro-death functions, which involves differential interactions with caspase-3.

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Combined and Individual Mitochondrial HSP60 and HSP10 Expression in Cardiac Myocytes Protects Mitochondrial Function and Prevents Apoptotic Cell Deaths Induced by Simulated Ischemia-Reoxygenation

Cited by 255 publications

References 15 publications

Differential Effects of Mitochondrial Heat Shock Protein 60 and Related Molecular Chaperones to Prevent Intracellular β-Amyloid-induced Inhibition of Complex IV and Limit Apoptosis

Differential Effects of Mitochondrial Heat Shock Protein 60 and Related Molecular Chaperones to Prevent Intracellular β-Amyloid-induced Inhibition of Complex IV and Limit Apoptosis

Mitochondrial network in the heart

Cytosolic Accumulation of HSP60 during Apoptosis with or without Apparent Mitochondrial Release

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