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Glutathione reductase, redox homeostasis, and mitochondrial dysfunction

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
•O2- 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.