Cortisol Regulates Cerebral Mitochondrial Oxidative Phosphorylation and Morphology of the Brain in a Region-Specific Manner in the Ovine Fetus

Abstract

In adults, glucocorticoids are stress hormones that act, partly, through actions on mitochondrial oxidative phosphorylation (OXPHOS) to increase energy availability. Before birth, glucocorticoids are primarily maturational signals that prepare the fetus for new postnatal challenges. However, the role of the normal prepartum glucocorticoid rise in preparing mitochondria for the increased postnatal energy demands remains largely unknown. This study examined the effect of physiological increases in the fetal cortisol concentration on cerebral mitochondrial OXPHOS capacity near term (~130 days gestation, term ~145 days gestation). Fetal sheep were infused with saline or cortisol for 5 days at ~0.8 of gestation before the mitochondrial content, respiratory rates, abundance of the electron transfer system proteins and OXPHOS efficiency were measured in their cortex and cerebellum. Cerebral morphology was assessed by immunohistochemistry and stereology. Cortisol treatment increased the mitochondrial content, while decreasing Complex I-linked respiration in the cerebellum. There was no effect on the cortical mitochondrial OXPHOS capacity. Cortisol infusion had regional effects on cerebral morphology, with increased myelination in the cerebrum. The findings demonstrate the importance of cortisol in regulating the cerebral mitochondrial OXPHOS capacity prenatally and have implications for infants born preterm or after glucocorticoid overexposure due to pregnancy complications or clinical treatment.

Keywords: brain; cortisol; fetus; mitochondria.

Figure 1

Mitochondrial respiratory function in the cortex and cerebellum. Data presented as median and interquartile range with individual data points (black dots) for respiratory rates relative to citrate synthase (CS) activity in the cortex (A) and cerebellum (B) for leak respiration (CI_L), Complex I-linked respiration (CI_P), CI&CII-linked respiration (CI&CII_P) and CII_P-linked respiration (CII_P), leak state, oxidative phosphorylation (OXPHOS) coupling efficiency, the fraction of OXPHOS capacity attributable to CI and the fraction of OXPHOS capacity attributable to CII (CI and CII flux control ratios) from saline (open columns, n = 7) and cortisol-infused (filled columns, n = 6) fetuses at ~130 days of gestational age (dGA). * Significantly different from saline control, p < 0.05, t-test. One data point (Complex I Flux Control Ratio, control fetus) was detected as an outlier according to the ROUT method [18] and was removed from subsequent analysis.

Figure 2

Mitochondrial ETS complex and ANT1 abundance in the cerebellum and cortex. Data presented as median and interquartile range with individual data points (black dots) for relative protein abundance in the cerebellum (A) and cortex (B) from saline (open columns, n = 7) and cortisol-infused (filled columns, n = 6) fetuses at ~130 days of gestational age (dGA).