NR3C1/PRKACG-mediated impairment of mitochondrial quality control underlies stress-induced hypothalamic neuronal injury

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Abstract
The hypothalamus integrates autonomic, endocrine, and behavioral responses to stress, and stress-induced hypothalamic neuronal injury is implicated in various diseases. However, the underlying molecular mechanisms remain unclear. Mitochondria, as stress-sensitive organelles, play a critical role in cellular injury through structural and functional alterations. Here, we investigate how stress triggers mitochondrial quality control (MQC) dysfunction via glucocorticoid receptor (NR3C1) signaling, contributing to hypothalamic neuronal injury. Using acute and chronic stress rat models, we demonstrate that stress induces hypothalamic neuronal damage. Transmission electron microscopy and WB analysis reveal that stress promotes excessive mitochondrial fission while suppressing fusion, disrupting mitochondrial dynamics. At the cellular level, ChIP-Seq and siRNA experiments confirm that glucocorticoids (GCs) downregulate PRKACG (protein kinase A catalytic subunit gamma) expression via NR3C1-mediated transcriptional repression, reducing DRP1 (dynamin-related protein 1) phosphorylation at Ser637 and leading to aberrant mitochondrial fission. Furthermore, acute and chronic stress differentially activate mitophagy pathways, resulting in mitochondrial depletion. Intriguingly, neuronal death shifts from apoptosis to necroptosis under prolonged stress. In conclusion, our findings establish that NR3C1/PRKACG-mediated MQC dysfunction is a key mechanism in stress-induced hypothalamic neuronal injury. This study not only elucidates how GCs disrupt MQC but also advances our understanding of mitochondrial dysregulation in stress-related neuronal damage, providing a foundation for future mechanistic and therapeutic investigations.

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