Sex dependent alterations in mitochondrial electron transport chain proteins following neonatal rat cerebral hypoxic-ischemia

Males are more susceptible to brain mitochondrial bioenergetic dysfunction following neonatal cerebral hypoxic-ischemia (HI) than females. Mitochondrial biogenesis has been implicated in the cellular response to HI injury, but sex differences in biogenesis following HI have not been described. We tested the hypothesis that mitochondrial biogenesis or the expression of mitochondrial electron transport chain (ETC) proteins are differentially stimulated in the brains of 8 day old male and female rats one day following HI, and promoted by treatment with acetyl-L-carnitine (ALCAR). There were no sex differences in mitochondrial mass, as reflected by the ratio of mitochondrial to nuclear DNA (mtDNA/nDNA) and citrate synthase enzyme activity present one day following HI or sham surgery. There was an increase in mtDNA/nDNA, however, in the hypoxic and ischemic (ipsilateral) hemisphere after HI in both male and female brains at one day post-injury, which was suppressed by ALCAR. Citrate synthase activity was increased in the ipsilateral hemisphere of ALCAR treated male and female brain. Most importantly, the levels of representative mitochondrial proteins present in ETC complexes I, II and IV increased substantially one day following HI in female, but not male brain. This sex difference is consistent with the increase in the mitochondrial biogenesis-associated transcription factor NRF-2/GABP alpha following HI in females, in contrast to the decrease observed with males. In conclusion, the female sex-selective increase in ETC proteins following HI may at least partially explain the relative female resilience to mitochondrial respiratory impairment and neuronal death that occur after HI.