Dissertation/Thesis Abstract

Glutathione reductase, redox homeostasis, and mitochondrial dysfunction
by Ren, Pei, M.S., Kent State University, 2013, 46; 1555282
Abstract (Summary)

Overproduction of reactive oxygen species and increasing oxidative stress have emerged as the major factors leading to mitochondrial dysfunction during myocardial ischemia and reperfusion (I/R) injury. Under normal physiology conditions, glutathione (GSH) concentration is high in the mitochondrial redox pool However, GSH is oxidized to GSSG (oxidized glutathione) upon the exposure of oxidative stress, such as the overproduction of ·O 2 and ·O2 derived oxidants during I/R injury. Decreased GSH/GSSG ratio was found to enhance protein S-glutathiolation of complex I, which serves as a redox marker for mitochondrial dysfunction in vivo. Excess GSSG normally is recycled to GSH by mitochondrial glutathione reductase (GR2 isoform) in maintaining the basal level of complex I S-glutathiolation and redox homeostasis in mitochondria. Available evidence has indicated that protein S-glutathiolation in vitro can be induced by GSSG through the reaction of protein thiol-disulfide exchange. Thus we hypothesize that GR2 deficiency will impair mitochondrial function and subsequently heart function via enhancing S-glutathiolation of complex I. Furthermore, there is little understanding toward the role of GR2 in mitochondrial dysfunction, and the mechanism of GR2-mediated S-glutathiolation of Complex I. We first performed the study in the heart of a post-ischemic rat model to evaluate the alteration in GR2 activity after myocardial infarction. Rats received intraperitoneal administration of 3-bischoloroethyl-1-nitrosourea(BCNU), a GR2 inhibitor. We observed systolic dysfunction, decreased respiratory control ratio, and increased ·O2 generation under the condition of state 3 respiration after BCNU treatment. We also found decreased GSH/GSSG ratio, increased redox activity and increased Complex I S-glutathiolation. These data suggest that mitochondrial GR deficiency and mitochondrial oxidative stress and associated redox modification are the molecular mechanisms of BCNU induced systolic dysfunction. The above studies were further evaluated using the animal model of cardiac-specific SOD2 transgenic mice. The overexpression of SOD2 reversed the BCNU-induced GR2 inhibition and mitochondrial impairment.

Indexing (document details)
Advisor: Chen, Yeong-Renn
Commitee: Bratz, Ian, Carroll, Richard
School: Kent State University
Department: Biomedical Sciences
School Location: United States -- Ohio
Source: MAI 52/06M(E), Masters Abstracts International
Source Type: DISSERTATION
Subjects: Pharmacology, Biochemistry, Biomedical engineering
Keywords: Glutathione, Mitochondrial dysfunction, Myocardial ischemia, Oxidative stress, Reactive oxygen species
Publication Number: 1555282
ISBN: 978-1-303-87369-0
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