Dynamic regulation of mitochondrial function by glucocorticoids

Abstract

Glucocorticoids play an important biphasic role in modulating neural plasticity; low doses enhance neural plasticity and spatial memory behavior, whereas chronic, higher doses produce inhibition. We found that 3 independent measures of mitochondrial functionmitochondrial oxidation, membrane potential, and mitochondrial calcium holding capacity-were regulated by long-term corticosterone (CORT) treatment in an inverted ''U''-shape. This regulation of mitochondrial function by CORT correlated with neuroprotection; that is, treatment with low doses of CORT had a neuroprotective effect, whereas treatment with high doses of CORT enhanced kainic acid (KA)-induced toxicity of cortical neurons. We then undertook experiments to elucidate the mechanisms underlying these biphasic effects and found that glucocorticoid receptors (GRs) formed a complex with the anti-apoptotic protein Bcl-2 in response to CORT treatment and translocated with Bcl-2 into mitochondria after acute treatment with low or high doses of CORT in primary cortical neurons. However, after 3 days of treatment, high, but not low, doses of CORT resulted in decreased GR and Bcl-2 levels in mitochondria. As with the in vitro studies, Bcl-2 levels in the mitochondria of the prefrontal cortex were significantly decreased, along with GR levels, after long-term treatment with high-dose CORT in vivo. These findings have the potential to contribute to a more complete understanding of the mechanisms by which glucocorticoids and chronic stress regulate cellular plasticity and resilience and to inform the future development of improved therapeutics.allostasis ͉ Bcl-2 ͉ mitochondria ͉ mood disorders ͉ glucocorticoid receptor

Neuroprotective effects of Tualang honey against oxidative stress and memory decline in young and aged rats exposed to noise stress

“…Significant difference between stress control and stress treated with honey ( ♣ P < .05). both glucocorticoid exposure and oxidative stress may induce neuronal oxidative stress through enhanced mitochondrial respiration and oxidative phosphorylation [50], and promote gliogenesis over neurogenesis in hippocampal neural stem cell progenitors [51,52]. Correspondingly, we demonstrated that the stressed rats possessed a lower number of pyramidal neurons in the hippocampus as well as in the mPFC compared to the nonstressed rats.…”

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

“…In both cultured neurons and in prefrontal cortex tissue, GC treatment showed a biphasic effect on mitochondrial oxidation, membrane potential, and calcium capacity, with lower doses improving these measures and higher or chronic doses and treatments causing deficits. These effects were correlated with the neuroprotective effects of the GC corticosterone (15). Previous studies have established that GRs can alter the transcription of mitochondrial genes in cultured cells, but GR regulation of mtDNA transcription has not yet been confirmed as occurring in vivo (13).…”

“…Steroid hormone receptors, including estrogen receptors and GRs, translocate into brain mitochondria. Studies in cultured cells suggest that mtDNA contains GC response elements (GREs) and that these may have a functional role in regulating mtDNA transcription (13)(14)(15)(16)(17)(18). In both cultured neurons and in prefrontal cortex tissue, GC treatment showed a biphasic effect on mitochondrial oxidation, membrane potential, and calcium capacity, with lower doses improving these measures and higher or chronic doses and treatments causing deficits.…”

A kinesin signaling complex mediates the ability of GSK-3β to affect mood-associated behaviors

“…Immunoprecipitation was performed as previously described with minor modifications (37). Detailed methods are provided in SI Materials and Methods.…”