Mitochondria-specific transgenic overexpression of phospholipid hydroperoxide glutathione peroxidase (GPx4) attenuates ischemia/reperfusion-associated cardiac dysfunction.
ABSTRACT Ischemia/reperfusion (I/R) injury elicits damage to mitochondria. Antioxidants provide protection from I/R-induced mitochondrial damage. The goal of this study was to determine the impact of mitochondria-specific overexpression of GPx4 (PHGPx) on cardiac function following I/R. Transgenic mice were created in which PHGPx was overexpressed solely in the mitochondrion (mPHGPx). MPHGPx and littermate control hearts were subjected to global no-flow ischemia (20 min) followed by reflow reperfusion (30, 60, and 90 min). Following I/R, mPHGPx hearts possessed significantly better rates of contraction, developed pressures, and peak-systolic pressures as compared to controls (P<0.05). No differences were observed in rates of relaxation or end-diastolic pressures. Lipid peroxidation was significantly lower in mitochondria from mPHGPx hearts as compared to controls, following I/R (P<0.05). Electron transport chain (ETC) complex I, III, and IV activities were significantly higher in mPHGPx hearts as compared to controls, following I/R (P<0.05). MPHGPx overexpression enhanced ETC complex I, III, and IV activities in subsarcolemmal mitochondria (SSM; P<0.05), and ETC complex I and III activities in interfibrillar mitochondria (IFM; P<0.05) following I/R. These results indicate that mitochondria-specific GPx4 overexpression protects cardiac contractile function and preserves ETC complex activities following I/R. These results provide further rationale for the use of mPHGPx as a therapeutic protectant.
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ABSTRACT: Mitochondrial redox metabolism has long been considered to play important roles in mammalian aging and the development of age-related pathologies in the major oxidative organs. Both genetic and dietary manipulations of mitochondrial redox metabolism have been associated with the extension of lifespan. Here we provide a broad overview of the circumstantial evidence showing associations between mitochondrial reactive oxygen species (ROS) metabolism, aging and longevity. We address most aspects of mitochondrial ROS metabolism, from superoxide production, to ROS detoxification and the repair/removal of ROS-mediated macromolecular damage. Finally, we discuss the effects of dietary manipulations (e.g. caloric restriction, methionine restriction), dietary deficiencies (e.g. folate) and dietary supplementation (e.g. resveratrol) on mitochondrial ROS metabolism and lifespan.Mechanisms of ageing and development 02/2010; 131(4):242-52. DOI:10.1016/j.mad.2010.02.005 · 3.51 Impact Factor
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ABSTRACT: Selenium, as an integral part of selenoproteins, is essential for mammals. Unequivocal evidence had been provided more than a decade ago when it was proven that mice incapable of producing any of the 24 selenoproteins failed to develop beyond the gastrulation stage (E6.5). Since then, more specific attempts have been made to unmask novel and essential functions of individual selenoproteins in mice. Genetic disruption of glutathione peroxidase 4 (GPx4; also referred to as phospholipid hydroperoxide glutathione peroxidase, PHGPx) in mice showed for the first time that a specific selenoenzyme is in fact required for early embryonic development. Later on, systemic ablation of cytosolic thioredoxin reductase (Txnrd1) or mitochondrial thioredoxin reductase (Txnrd2) yielded embryonic lethal phenotypes. Beside those three, no other selenoproteins have been found being indispensable for murine development so far. This review aims at summarizing mainly the in vivo findings on these important mammalian selenoenzymes, which have not only common attributes of being required for embryogenesis, but that they are also instrumental in the regulation of cellular redox metabolism.Biochimica et Biophysica Acta 11/2009; DOI:10.1016/j.bbagen.2009.05.001 · 4.66 Impact Factor
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ABSTRACT: A collection of 41 Ralstonia solanacearum (RS) strains isolated from bacterial wilted tobacco collected in 10 Chinese provinces was investigated based on their biovar, heterogeneity within an axenic laboratory culture, and growth to determine the current distribution pattern of tobacco RS strains in China as well as to provide theoretic guidance to disease control. Of the 41 isolates, 18 belonged to typical biovars (bv1:1, bv2:4, bv3:10, and bv5:3) and 23 to atypical biovars. This classification was based on their ability to oxidize three hexose (lactose, maltose, and cellobiose) and three disaccharides (manitol, sobitol, and dulcite). Of the 23 strains in atypical biovars, a group closed to bv3 (utilized all the other five carbon sources except dulcite) accounted for 73.9%. Heterogeneity within an axenic culture determined through flow cytometry was initially used for RS. The results showed that the descending order rates of heterogeneity index were 19.5, 24.4, 31.7, and 24.4%, respectively. Growth of different strains in static culture showed that the rates of absorbance value from strong to weak were 58.3, 31.7, and 10%, respectively. All the results above showed that the physiological characteristics of RS strains isolated from different geographical regions were diverse.