Cytosolic Escape of Mitochondrial DNA Triggers cGAS-STING Pathway-Dependent Neuronal PANoptosis in Response to Intermittent Hypoxia.
Neurochem Res
; 49(8): 2228-2248, 2024 Aug.
Article
em En
| MEDLINE
| ID: mdl-38833090
ABSTRACT
Intermittent hypoxia (IH) is the predominant pathophysiological disturbance in obstructive sleep apnea (OSA), characterized by neuronal cell death and neurocognitive impairment. We focus on the accumulated mitochondrial DNA (mtDNA) in the cytosol, which acts as a damage-associated molecular pattern (DAMP) and activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a known trigger for immune responses and neuronal death in degenerative diseases. However, the specific role and mechanism of the mtDNA-cGAS-STING axis in IH-induced neural damage remain largely unexplored. Here, we investigated the involvement of PANoptosis, a novel type of programmed cell death linked to cytosolic mtDNA accumulation and the cGAS-STING pathway activation, in neuronal cell death induced by IH. Our study found that PANoptosis occurred in primary cultures of hippocampal neurons and HT22 cell lines exposed to IH. In addition, we discovered that during IH, mtDNA released into the cytoplasm via the mitochondrial permeability transition pore (mPTP) activates the cGAS-STING pathway, exacerbating PANoptosis-associated neuronal death. Pharmacologically inhibiting mPTP opening or depleting mtDNA significantly reduced cGAS-STING pathway activation and PANoptosis in HT22 cells under IH. Moreover, our findings indicated that the cGAS-STING pathway primarily promotes PANoptosis by modulating endoplasmic reticulum (ER) stress. Inhibiting or silencing the cGAS-STING pathway substantially reduced ER stress-mediated neuronal death and PANoptosis, while lentivirus-mediated STING overexpression exacerbated these effects. In summary, our study elucidates that cytosolic escape of mtDNA triggers cGAS-STING pathway-dependent neuronal PANoptosis in response to IH, mainly through regulating ER stress. The discovery of the novel mechanism provides theoretical support for the prevention and treatment of neuronal damage and cognitive impairment in patients with OSA.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
DNA Mitocondrial
/
Transdução de Sinais
/
Citosol
/
Proteínas de Membrana
/
Neurônios
/
Nucleotidiltransferases
Limite:
Animals
Idioma:
En
Revista:
Neurochem Res
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China