Aluminum induces oxidative mitochondrial DNA release via a HIF-1α-related pathway to activate NLRP3 inflammasomes in astrocytes

Abstract Aluminum compounds are widely distributed in nature and are frequently used in daily life. However, they are environmental etiologic factors for neurodegenerative diseases. Aluminum causes neuroinflammation, but the roles of astrocytes in this process have not yet been fully established. We established rat models of subchronic aluminum exposure by allowing them to drink water containing AlCl3 for 12 w. Primary astrocytes were isolated and treated with AlCl3. In vitro, YC-1 was used as an inhibitor of HIF-1α. Aluminum exposure activated astrocytes, suppressed α-KGDH activities while increasing SDH activities, which stabilized HIF-1α to enhance HIF-1α levels and its colocalization with PKM2 in the nucleus. Furthermore, activated PKM2 induced the phosphorylation of C-Myc at Ser62 to prevent its degradation, which upregulated CLIC4 protein levels to disrupt mitochondrial membrane potential. During this process, OX-mt DNA was released. In the cytoplasm, OX-mt DNA bound and stimulated the NLRP3 inflammasome, resulting in more IL-1β release to trigger neuroinflammation. Treatment with YC-1 reversed these outcomes. These findings imply that astrocytes have an important role in aluminum-induced neuroinflammation.