Aluminum induced oxidative mitochondrial DNA release mediated by HIF-1α-related pathway to activate NLRP3 inflammasome in astrocytes [post]

Ziyue Liu, Chenyu Hao, Xiaoying Zhu, Yushuai Song, Wudi Hao, Shengwen Wu, Jinghua Yang, Xiaobo Lu, Cuihong Jin
2022 unpublished
Aluminum compounds are widely distributed in nature and applied frequently in daily life, which are considered as environmental pathogenic factor of neurodegenerative diseases. Previous studies have suggested that aluminum can cause neuroinflammation, but whether astrocytes could play an important role is still obscure. Here, the rat model of subchronic aluminum exposure was established by drinking water containing AlCl3 for 12 w. Primary astrocytes were isolated and treated with AlCl3. YC-1
more » ... adopted as an inhibitor of HIF-1α in vitro experiments. In this study, aluminum exposure could activate astrocytes, decrease α-KGDH activity while increase SDH activity, which stabilized HIF-1α to enhance HIF-1α level and its colocalization with PKM2 in nucleus. Further, PKM2 was activated to phosphorylate C-Myc at Ser62 to prevent its degradation, which upregulated CLIC4 protein level to reduce mitochondrial membrane potential and OX-mt DNA was released. In the cytoplasm, OX-mt DNA could bind to and stimulate NLRP3 inflammasome, resulting in more IL-1β release to trigger neuroinflammation, and the intervention of YC-1 could rescue these impairments. That is, astrocytes play an important role in aluminum-induced neuroinflammation.
doi:10.21203/rs.3.rs-1673190/v1 fatcat:4rof7ihrczdkhhtil6i6tpuegm