Neonatal hypoxia–ischemia induces sex-related changes in rat brain mitochondria

Weis, Simone Nardin; Pettenuzzo, Letícia Ferreira; Krolow, Rachel; Valentim, Lauren Martins; Mota, Carina de Souza; Dalmaz, Carla; Wyse, Ângela T. S.; Netto, Carlos Alexandre

doi:10.1016/j.mito.2011.10.002

Cited by 49 publications

(47 citation statements)

References 55 publications

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“…They proposed that astrocytic malfunction may predict severity of injury after HI and contribute to sex differences in outcome [55]. Weis et al [56] found significantly lower activity of electron transport chain complexes I–III in brains of male rat pups compared to female pups 18 hours after HI on PND 7. However, it should be noted that activity of the electron transport chain was decreased in the ipsilateral cortex and hippocampus of both males and females[56].…”

Section: Discussionmentioning

confidence: 99%

“…Weis et al [56] found significantly lower activity of electron transport chain complexes I–III in brains of male rat pups compared to female pups 18 hours after HI on PND 7. However, it should be noted that activity of the electron transport chain was decreased in the ipsilateral cortex and hippocampus of both males and females[56]. Male rat pups exhibited a more extensive impairment of mitochondrial respiration than females at 20 hours after HI [27].…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotective Effects of Acetyl-<smlcap>L</smlcap>-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats

Tang

Lü

et al. 2016

Dev Neurosci

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Perinatal hypoxia ischemia (HI) is a significant cause of brain injury in surviving infants. Although hypothermia improves outcomes in some infants, additional therapies are needed since about 40% of infants still have a poor outcome. Acetyl-L-carnitine (ALCAR), an acetylated derivative of L-carnitine, protected against early changes in brain metabolites and mitochondrial function after HI on postnatal day (PND) 7 in a rat pup model of near-term HI injury. However, its efficacy in long-term structural and functional outcomes remains unexplored. We determined the efficacy of ALCAR therapy administered to rat pups after HI at PND 7, using both longitudinal in vivo magnetic resonance imaging and behavioral tests, in male and female rats. HI led to sex-specific behavioral impairment, with males exhibiting more global functional deficits than females. Interestingly, HI reduced the volume of the contralateral hemisphere in males only, suggesting that the brain injury is more diffuse in males than in females. Treatment with ALCAR improved both morphological and functional outcomes in both male and female rats. These results suggest that ALCAR may be a potential therapy for clinical use since the treatment attenuated the moderate injury produced under the experimental conditions used and improved the functional outcome in preclinical studies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Acetyl-<smlcap>L</smlcap>-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats

Tang

Lü

et al. 2016

Dev Neurosci

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“…These findings highlight the possibility that females are hardwired for favorable nuclear to mitochondrial coordination of critical mitochondrial respiratory subunits in response to stress compared to males. The few studies assessing sex differences in mitochondrial function following injury reveal substantial differences in mitochondrial membrane potential, enzyme activity and respiration between male and female rodents after cerebral neonatal hypoxic ischemia (Weis et al 2012; Demarest et al 2013). Therefore, the focus of this review is to examine the literature on sexually dimorphic phenomena relevant to metabolic and mitochondrial function in the context of well-established mechanisms of CNS injury.…”

Section: Introductionmentioning

confidence: 99%

Sex differences in mitochondrial (dys)function: Implications for neuroprotection

Demarest

McCarthy

2014

J Bioenerg Biomembr

143

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Decades of research have revealed numerous differences in brain structure size, connectivity and metabolism between males and females. Sex differences in neurobehavioral and cognitive function after various forms of central nervous system (CNS) injury are observed in clinical practice and animal research studies. Sources of sex differences include early life exposure to gonadal hormones, chromosome compliment and adult hormonal modulation. It is becoming increasingly apparent that mitochondrial metabolism and cell death signaling are also sexually dimorphic. Mitochondrial metabolic dysfunction is a common feature of CNS injury. Evidence suggests males predominantly utilize proteins while females predominantly use lipids as a fuel source within mitochondria and that these differences may significantly affect cellular survival following injury. These fundamental biochemical differences have a profound impact on energy production and many cellular processes in health and disease. This review will focus on the accumulated evidence revealing sex differences in mitochondrial function and cellular signaling pathways in the context of CNS injury mechanisms and the potential implications for neuroprotective therapy development.

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“…Cell death in these models is a consequence of the reoxygenation process that follows ischemia67, thus, sex differences in mitochondrial function and membrane composition may underlie these differential outcome. Indeed, male pups present a deeper deficit in electron chain transport and a weaker anti-oxidant system than females after HI686970. From our results, CL molecular species in males are enriched in PUFAs and therefore more sensitive to oxidative stress71.…”

Section: Discussionmentioning

confidence: 53%

Developmental Sex Differences in the Metabolism of Cardiolipin in Mouse Cerebral Cortex Mitochondria

Acaz‐Fonseca

Ortiz-Rodriguez

López-Rodríguez

et al. 2017

Sci Rep

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Cardiolipin (CL) is a mitochondrial-specific phospholipid. CL content and acyl chain composition are crucial for energy production. Given that estradiol induces CL synthesis in neurons, we aimed to assess CL metabolism in the cerebral cortex (CC) of male and female mice during early postnatal life, when sex steroids induce sex-dimorphic maturation of the brain. Despite the fact that total amount of CL was similar, its fatty acid composition differed between males and females at birth. In males, CL was more mature (lower saturation ratio) and the expression of the enzymes involved in synthetic and remodeling pathways was higher, compared to females. Importantly, the sex differences found in CL metabolism were due to the testosterone peak that male mice experience perinatally. These changes were associated with a higher expression of UCP-2 and its activators in the CC of males. Overall, our results suggest that the perinatal testosterone surge in male mice regulates CL biosynthesis and remodeling in the CC, inducing a sex-dimorphic fatty acid composition. In male’s CC, CL is more susceptible to peroxidation, likely explaining the testosterone-dependent induction of neuroprotective molecules such as UCP-2. These differences may account for the sex-dependent mitochondrial susceptibility after perinatal hypoxia/ischemia.

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Neonatal hypoxia–ischemia induces sex-related changes in rat brain mitochondria

Cited by 49 publications

References 55 publications

Neuroprotective Effects of Acetyl-<smlcap>L</smlcap>-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats

Neuroprotective Effects of Acetyl-<smlcap>L</smlcap>-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats

Sex differences in mitochondrial (dys)function: Implications for neuroprotection

Developmental Sex Differences in the Metabolism of Cardiolipin in Mouse Cerebral Cortex Mitochondria

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