# Astrocyte Bioenergetic Remodeling as a Central Trait of Disrupted Glucocorticoid Signaling: Mechanisms and Implications for Stress Vulnerability

## TL;DR

This paper explores how stress hormones like glucocorticoids affect astrocyte metabolism, leading to brain dysfunction in stress-related disorders.

## Contribution

The paper introduces a biphasic model of astrocyte metabolic changes in response to glucocorticoids, linking these changes to stress vulnerability.

## Key findings

- Acute glucocorticoid exposure boosts astrocyte metabolism through glycolysis and mitochondrial activation.
- Prolonged exposure shifts metabolism toward branched-chain amino acids and lipids, increasing ROS and impairing astrocyte function.
- Disrupted astrocyte metabolism may contribute to synaptic and energy imbalances in neuropsychiatric disorders.

## Abstract

Glucocorticoids (GCs) are central to the organism's adaptation to stress, coordinating systemic energy distribution and neuroendocrine signaling. While acute effects of GCs are adaptive, chronic GC exposure is increasingly recognized as an important factor contributing to the pathophysiology of neuropsychiatric disorders, such as post‐traumatic stress disorder (PTSD) or major depressive disorder (MDD). A piling evidence points to astrocytes as a central integrator of brain response to stress hormones, including GCs. In this review, we discuss a biphasic regulation of astrocyte metabolism by GCs. According to the hypothesis, astrocytes undergo metabolic adaptations in response to GC: acute exposure leads to the enhancement of astrocyte metabolism through upregulation of glycolysis, mitochondrial activation, and glutamate clearance. In turn, prolonged GC exposure induces a metabolic shift toward branched‐chain amino acid and lipid catabolism, promoting mitochondrial reactive oxygen species (ROS) production and impairing key homeostatic functions, including the astrocyte‐neuron lactate shuttle and calcium signaling. Progressive disruption of astrocytes' supporting function may subsequently lead to synaptic dysregulation and energy imbalance in stress‐related brain pathology. We postulate that a detailed understanding of this dynamic regulation is necessary for targeting astrocyte‐specific metabolic mechanisms in neuropsychiatric disorders.

Low/brief glucocorticoid (GC) elevations can enhance mitochondrial output (↑ oxygen consumption rate, OCR; ↑ mitochondrial membrane potential, ΔΨm) and Ca2+ buffering, in part via glucocorticoid receptor (GR) trafficking to mitochondria in complexes with Bcl2 and Bag1. With increasing GC dose/duration, an intermediate “substrate flexibility” program may preserve bioenergetic output while shifting metabolism toward reduced pyruvate oxidation (↑ pyruvate dehydrogenase kinase 4, PDK4; ↑ pyruvate dehydrogenase phosphorylation, PDH‐P) and greater reliance on alternative substrates (branched‐chain amino acids, fatty‐acid). Under prolonged/high GC exposure, GR–Bcl2/Bag1 routing is reduced, mitochondrial output and Ca2+ buffering decline, redox balance worsens (↑ reactive oxygen species, ROS, ↓ antioxidant enzymes), and mitochondrial quality control is impaired, contributing to reduced ATP availability and increased vulnerability. Abbreviations: ATP, adenosine triphosphate; BCAA, branched‐chain amino acids; Bcl2, B‐cell lymphoma 2; DRP1, dynamin‐related protein 1; GC, glucocorticoid; GPx, glutathione peroxidase; GR, glucocorticoid receptor; MFN1/2, mitofusin‐1/2; OCR, oxygen consumption rate; OPA1, optic atrophy 1; PDH, pyruvate dehydrogenase; PDH‐P, phosphorylated pyruvate dehydrogenase; PDK4, pyruvate dehydrogenase kinase 4; ROS, reactive oxygen species; Cu/Zn‐SOD, copper/zinc superoxide dismutase; BNIP3L/NIX, BCL2 interacting protein 3‐like (NIP3‐like protein X); ΔΨm, mitochondrial membrane potential. Arrows indicate qualitative trends along a dose/duration continuum; thresholds vary by paradigm. *Items marked with an asterisk reflect mechanisms supported strongly in neuronal/whole‐brain systems and are hypothesized to contribute analogously in astrocytes, where direct cell‐type–resolved evidence remains limited.