MITOCHONDRIAL SUSCEPTIBILITY TO OXIDATIVE STRESS EXACERBATES CEREBRALINFARCTION 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 f low, have been shown to be both the sites of superoxide anion (O-2(-)) production and the target of free radical attacks. We evaluated these mechanisms in an in vivo cerebral ischemia model, using mutant mice w ith a heterozygous knockout gene (Sod2 -/+) encoding mitochondrial man ganese superoxide dismutase (Mn-SOD). Sod2 -/+ mice demonstrated a pro minent increase in O-2(-) production under normal physiological condit ions and in ischemia, as evidenced by specific oxidation of a fluoresc ent probe, hydroethidine, reflecting decreased activity of Mn-SOD. A m itochondrial viability assay that used rhodamine 123, which is accumul ated by transmembrane potential of viable mitochondria, demonstrated a ccelerated development of mitochondrial injury. This rapid progress of ischemic injury resulted in exacerbation of infarct size and hemisphe re enlargement, causing advanced neurological deficits but without alt ering DNA fragmentation induction. The present study suggests that O-2 (-) overproduced in a mitochondrial compartment, when uncoupled from a ntioxidant defenses, induces impairment of mitochondrial function and causes exacerbation of cerebral infarction after ischemia.