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While cell death signaling pathways are known to be sexually dimorphic, a sex\u2010dependent pathophysiological mechanism preceding the majority of secondary cell death has yet to be described. Mitochondrial dysfunction contributes to cell death following cerebral hypoxic\u2010ischemia (<jats:styled-content style=\"fixed-case\">HI<\/jats:styled-content>). Several lines of evidence suggest that there are sex differences in the mitochondrial metabolism of adult mammals. Therefore, this study tested the hypothesis that brain mitochondrial respiratory impairment and associated oxidative stress is more severe in males than females following <jats:styled-content style=\"fixed-case\">HI<\/jats:styled-content>. Maximal brain mitochondrial respiration during oxidative phosphorylation was two\u2010fold more impaired in males following <jats:styled-content style=\"fixed-case\">HI<\/jats:styled-content>. The endogenous antioxidant glutathione was 30% higher in the brain of sham females compared to males. Females also exhibited increased glutathione peroxidase (<jats:styled-content style=\"fixed-case\">GP<\/jats:styled-content>x) activity following <jats:styled-content style=\"fixed-case\">HI<\/jats:styled-content> injury. Conversely, males displayed a reduction in mitochondrial <jats:styled-content style=\"fixed-case\">GP<\/jats:styled-content>x4 protein levels and mitochondrial <jats:styled-content style=\"fixed-case\">GP<\/jats:styled-content>x activity. Moreover, a 3\u20134\u2010fold increase in oxidative protein carbonylation was observed in the cortex, perirhinal cortex, and hippocampus of injured males, but not females. These data provide the first evidence for sex\u2010dependent mitochondrial respiratory dysfunction and oxidative damage, which may contribute to the relative male susceptibility to adverse long\u2010term outcomes following <jats:styled-content style=\"fixed-case\">HI<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13590-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\nLower basal GSH levels, lower post\u2010hypoxic mitochondrial glutathione peroxidase (mtGPx) activity, and mitochondrial glutathione peroxidase 4 (mtGPx4) protein levels may contribute to the susceptibility of the male brain to oxidative damage and mitochondrial dysfunction following neonatal hypoxic\u2010ischemia (HI). Treatment of male pups with acetyl\u2010L\u2010carnitine (ALCAR) protects against the loss of mtGPx activity, mtGPx4 protein, and increases in protein carbonylation after HI. These findings provide novel insight into the pathophysiology of sexually dimorphic outcomes following HI.\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13590","type":"journal-article","created":{"date-parts":[[2016,2,26]],"date-time":"2016-02-26T08:22:25Z","timestamp":1456474945000},"page":"714-729","source":"Crossref","is-referenced-by-count":82,"title":["Sex\u2010dependent mitochondrial respiratory impairment and oxidative stress in a rat model of neonatal hypoxic\u2010ischemic encephalopathy"],"prefix":"10.1111","volume":"137","author":[{"given":"Tyler G.","family":"Demarest","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and the Center for Shock, Trauma, and Anesthesiology Research (S.T.A.R.) 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