Chronic Stress Causes Sex-Specific and Structure-Specific Alterations in Mitochondrial Respiratory Chain Activity in Rat Brain

Abstract

Chronic restraint stress (CRS) induces a variety of changes in brain function, some of which are mediated by glucocorticoids. The response to stress occurs in a sex-specific way, and may include mitochondrial and synaptic alterations. The synapse is highly dependent on mitochondrial energy supply, and when mitochondria become dysfunctional, they orchestrate cell death. This study aimed to investigate the CRS effects on mitochondrial respiratory chain activity, as well as mitochondrial potential and mass in cell body and synapses using hippocampus, cortex and striatum of male and female rats. Rats were divided into non-stressed (control) and stressed group (CRS during 40 days). Results showed that CRS increased complex I-III activity in hippocampus. We also observed an interaction between CRS and sex in the striatal complex II activity, since CRS induced a reduction in complex II activity in males, while in females this activity was increased. Also an interaction was observed between stress and sex in cortical complex IV activity, since CRS induced increased activity in females, while it was reduced in males. Glucocorticoid receptor (GR) content in cortex and hippocampus was sexually dimorphic, with female rats presenting higher levels compared to males. No changes were observed in GR content, mitochondrial potential or mass of animals submitted to CRS. It was concluded that CRS induced changes in respiratory chain complex activities, and some of these changes are sex-dependent: these activities are increased in the striatal mitochondria by CRS protocol mainly in females, while in males it is decreased.

Bag‐1 mediates glucocorticoid receptor trafficking to mitochondria after corticosterone stimulation: Potential role in regulating affective resilience

“…Mitochondria play a critical role in neurogenesis and neuronal functions, such as energy generation, calcium homeostasis, and apoptosis (Toescu et al., 2004; Uguz et al., 2016). Stress mediated by GCs may lead to a biphasic ‘inverted U shape’ response of mitochondria, while lower doses enhances mitochondrial functions, chronic, higher doses produce inhibition of these functions and further modulate neural plasticity and activity (de Souza Mota et al., 2017; Du, et al., 2009; Jeanneteau et al., 2016). Mitochondrial dysfunction is recognized as a part of damaged neuroendocrine stress response, which may involve action of GCs (Adzic et al., 2009).…”

Sexual differences in mitochondrial and related proteins in rat cerebral microvessels: A proteomic approach

“…1–10 Previous studies have shown that mitochondrial numbers and DNA, mitochondrial-mediated signaling, and mitochondrial respiration are greater in female when compared to male large cerebral arteries in rats. 11–13 Also, mitochondrial responses to pathological events such as experimental strokes differ in the large cerebral arteries of male and female rats. 14–18 However, it is unclear whether sex-dependent differences extend to the cerebral microcirculation.…”

p17/C18-ceramide–mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury

“…Moreover, an increasing number of studies in rodents and humans have demonstrated significant sex differences in response to mild TBIs, in which females show reduced susceptibility to secondary injuries and have overall better outcomes after primary injury compared with males ( 71–74 ). Hence, accumulating evidence suggests that the propensity of the mitochondrial stress response and mitophagy may vary between males and females, particularly under cellular stress conditions such as with TBI ( 75–78 ). However, it remains elusive how sex differences in the mitophagic response contribute to the development and progression of disease in rmTBI.…”