Mitochondria-specific transgenic overexpression of phospholipid hydroperoxide glutathione peroxidase (GPx4) attenuates ischemia/reperfusion-associated cardiac dysfunction

Dabkowski, Erinne R.; Williamson, Courtney L.; Hollander, John M.

doi:10.1016/j.freeradbiomed.2008.06.021

Cited by 134 publications

(138 citation statements)

References 49 publications

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“…Global overexpression of GPx1 or GPx4 is protective against a wide range of oxidative stressors both in vivo and in vitro (Ran et al 2004(Ran et al , 2006Lei and Cheng 2005;Dabkowski et al 2008). However, genetic manipulation of either GPx isoform gives results that are inconsistent with a role for increased GPx activity in life span extension (reviewed in Pérez et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endotherm species

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Richardson

Wiens

et al. 2010

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The free radical theory of ageing posits that accrual of oxidative damage underlies the increased cellular, tissue and organ dysfunction and failure associated with advanced age. In support of this theory, cellular resistance to oxidative stress is highly correlated with life span, suggesting that prevention or repair of oxidative damage might indeed be essential for longevity. To test the hypothesis that the prevention of oxidative damage underlies longevity, we measured the activities of the five major intracellular antioxidant enzymes in brain, heart and liver tissue of 14 mammalian and avian species with maximum life spans (MLSPs) ranging from 3 years to over 100 years. Our data set included Snell dwarf mice in which life span is increased by ∼50% compared to their normal littermates. We found that CuZn superoxide dismutase, the major cytosolic superoxide dismutase, showed no correlation with MLSP in any of the three organs. Similarly, neither glutathione peroxidase nor glutathione reductase activities correlated with MLSP. MnSOD, the sole mitochondrial superoxide dismutase in mammals and birds, was positively correlated with MLSP only for brain tissue. This same trend was observed for catalase. For all correlational data, effects of body mass and phylogenetic relatedness were removed using residual analysis and Felsenstein's phylogenetically independent contrasts. Our results are not consistent with a causal role for intracellular antioxidant enzymes in longevity, similar to recent reports from studies utilising genetic modifications of mice (Pérez et al., Biochim Biophys Acta 1790:1005-1014). However, our results indicate a specific augmentation of reactive oxygen species neutralising activities in brain associated with longevity.

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Section: Discussionmentioning

confidence: 99%

Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endotherm species

Page

Richardson

Wiens

et al. 2010

AGE

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“…Subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) were isolated from adult mouse hearts as previously described in detail (50). Size and membrane potential of SSM and IFM was determined by flow cytometry as previously reported (13,50). Calcium uptake and tBH-induced calcium release were assessed in isolated SSM and IFM.…”

Section: Animalsmentioning

confidence: 99%

Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death

Papanicolaou

Ngoh

Dabkowski

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death. Am J Physiol Heart Circ Physiol 302: H167-H179, 2012. First published October 28, 2011 doi:10.1152/ajpheart.00833.2011.-Molecular studies examining the impact of mitochondrial morphology on the mammalian heart have previously focused on dynamin related protein-1 (Drp-1) and mitofusin-2 (Mfn-2), while the role of the other mitofusin isoform, Mfn-1, has remained largely unexplored. In the present study, we report the generation and initial characterization of cardiomyocyte-specific Mfn-1 knockout (Mfn-1 KO) mice. Using electron microscopic analysis, we detect a greater prevalence of small, spherical mitochondria in Mfn-1 KO hearts, indicating that the absence of Mfn-1 causes a profound shift in the mitochondrial fusion/ fission balance. Nevertheless, Mfn-1 KO mice exhibit normal leftventricular function, and isolated Mfn-1 KO heart mitochondria display a normal respiratory repertoire. Mfn-1 KO myocytes are protected from mitochondrial depolarization and exhibit improved viability when challenged with reactive oxygen species (ROS) in the form of hydrogen peroxide (H2O2). Furthermore, in vitro studies detect a blunted response of KO mitochondria to undergo peroxideinduced mitochondrial permeability transition pore opening. These data suggest that Mfn-1 deletion confers protection against ROSinduced mitochondrial dysfunction. Collectively, we suggest that mitochondrial fragmentation in myocytes is not sufficient to induce heart dysfunction or trigger cardiomyocyte death. Additionally, our data suggest that endogenous levels of Mfn-1 can attenuate myocyte viability in the face of an imminent ROS overload, an effect that could be associated with the ability of Mfn-1 to remodel the outer mitochondrial membrane.

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“…Hearts were rinsed in PBS (pH 7.4), then blotted dry. SSM and IFM were isolated as previously described following the methods of Palmer et al (31) with minor modifications (11,12,42). Protein concentrations were determined using the Bradford method with BSA as a standard (3).…”

Section: Preparation Of Individual Mitochondrial Subpopulationsmentioning

confidence: 99%

Proteomic alterations of distinct mitochondrial subpopulations in the type 1 diabetic heart: contribution of protein import dysfunction

Baseler

Dabkowski

Williamson

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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110

140

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Diabetic cardiomyopathy is associated with increased risk of heart failure in type 1 diabetic patients. Mitochondrial dysfunction is suggested as an underlying contributor to diabetic cardiomyopathy. Cardiac mitochondria are characterized by subcellular spatial locale, including mitochondria located beneath the sarcolemma, subsarcolemmal mitochondria (SSM), and mitochondria situated between the myofibrils, interfibrillar mitochondria (IFM). The goal of this study was to determine whether type 1 diabetic insult in the heart influences proteomic make-up of spatially distinct mitochondrial subpopulations and to evaluate the role of nuclear encoded mitochondrial protein import. Utilizing multiple proteomic approaches (iTRAQ and two-dimensional-differential in-gel electrophoresis), IFM proteomic make-up was impacted by type 1 diabetes mellitus to a greater extent than SSM, as evidenced by decreased abundance of fatty acid oxidation and electron transport chain proteins. Mitochondrial phosphate carrier and adenine nucleotide translocator, as well as inner membrane translocases, were decreased in the diabetic IFM ( P < 0.05 for both). Mitofilin, a protein involved in cristae morphology, was diminished in the diabetic IFM ( P < 0.05). Posttranslational modifications, including oxidations and deamidations, were most prevalent in the diabetic IFM. Mitochondrial heat shock protein 70 (mtHsp70) was significantly decreased in diabetic IFM ( P < 0.05). Mitochondrial protein import was decreased in the diabetic IFM with no change in the diabetic SSM ( P < 0.05). Taken together, these results indicate that mitochondrial proteomic alterations in the type 1 diabetic heart are more pronounced in the IFM. Further, proteomic alterations are associated with nuclear encoded mitochondrial protein import dysfunction and loss of an essential mitochondrial protein import constituent, mtHsp70, implicating this process in the pathogenesis of the diabetic heart.

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Mitochondria-specific transgenic overexpression of phospholipid hydroperoxide glutathione peroxidase (GPx4) attenuates ischemia/reperfusion-associated cardiac dysfunction

Cited by 134 publications

References 49 publications

Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endotherm species

Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endotherm species

Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death

Proteomic alterations of distinct mitochondrial subpopulations in the type 1 diabetic heart: contribution of protein import dysfunction

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