Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency.
Mitochondrial injury has been implicated in ischemic neuronal injury. Mitochondria, producing adenosine triphosphate by virtue of electron flow, have been shown to be both the sites of superoxide anion (O2-) production and the target of free radical attacks. We evaluated these mechanisms in an in vivo cerebral ischemia model, using mutant mice with a heterozygous knock-out gene (Sod2 -/+) encoding mitochondrial manganese superoxide dismutase (Mn-SOD). Sod2 -/+ mice demonstrated a prominent increase in O2- production under normal physiological conditions and in ischemia, as evidenced by specific oxidation of a fluorescent probe, hydroethidine, reflecting decreased activity of Mn-SOD. A mitochondrial viability assay that used rhodamine 123, which is accumulated by transmembrane potential of viable mitochondria, demonstrated accelerated development of mitochondrial injury. This rapid progress of ischemic injury resulted in exacerbation of infarct size and hemisphere enlargement, causing advanced neurological deficits but without altering DNA fragmentation induction. The present study suggests that O2- overproduced in a mitochondrial compartment, when uncoupled from antioxidant defenses, induces impairment of mitochondrial function and causes exacerbation of cerebral infarction after ischemia.
Murakami
K
K
CNS Injury and Edema Research Center, Department of Neurological Surgery, University of California, School of Medicine, San Francisco, California 94143-0651, USA.
Kondo
T
T
Kawase
M
M
Li
Y
Y
Sato
S
S
Chen
S F
SF
Chan
P H
PH
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000201:enzymology; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism*; D002544:Cerebral Infarction / Q000209:etiology / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D053938:DNA Fragmentation; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D016296:Mutagenesis / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics*
D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase