Glucocorticoid impairs mitochondrial quality control in neurons

Abstract

Neurons are particularly vulnerable to mitochondrial dysfunction due to high energy demand and an inability to proliferate. Therefore, dysfunctional mitochondria cause various neuropathologies. Mitochondrial damage induces maintenance pathways to repair or eliminate damaged organelles. This mitochondrial quality control (MQC) system maintains appropriate morphology, localization, and removal/replacement of mitochondria to sustain brain homeostasis and counter progression of neurological disorders. Glucocorticoid release is an essential response to stressors for adaptation; however, it often culminates in maladaptation if neurons are exposed to chronic and severe stress. Long-term exposure to high levels of glucocorticoids induces mitochondrial dysfunction via genomic and nongenomic mechanisms. Glucocorticoids induce abnormal mitochondrial morphology and dysregulate fusion and fission. Moreover, mitochondrial trafficking is arrested by glucocorticoids and dysfunctional mitochondria are subsequently accumulated around the soma. These alterations lead to energy deficiency, particularly for synaptic transmission that requires large amounts of energy. Glucocorticoids also impair mitochondrial clearance by preventing mitophagy of damaged organelle and suppress mitochondrial biogenesis, resulting in the reduced number of healthy mitochondria. Failure to maintain MQC degrades brain function and contributes to neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. However, mechanisms of glucocorticoid action on the regulation of MQC during chronic stress conditions are not well understood. The present review discusses pathways involved in the impairment of MQC and the clinical significance of high glucocorticoid blood levels for neurodegenerative diseases.

Keywords: Glucocorticoid; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control (MQC); Mitochondrial trafficking; Mitophagy; Neurodegenerative disease.