Inhibition of SIRT1/PGC-1α Axis Exacerbates Fluorine and Aluminium Induced Neurotoxicity via Drp1-dependent Aggravated Mitochondrial Fission

Both fluorine (F) and aluminium (Al) exhibit neurotoxic effects. Fluorine and aluminium (FA) coexist in naturally and artificially polluted environments and potentially affect human cognitive functions. However, the mechanism through which FA exposure impairs spatial learning and memory of the second-generation offspring (F2) rats remains unknown. Mitochondria are critical for brain function and are responsible for energy production. Excessive mitochondrial fission can cause dysfunction and neuron damage. In this study, SD rats were exposed to FA, while NG108-15 cells were pretransfected with Peroxisome Proliferator-activated Receptor gamma coactivator-1α (PGC-1α) siRNA or the silent information regulator1 (SIRT1) siRNA or treated with mitochondrial division inhibitor-1 (Mdivi-1), and then exposed to FA. FA exposure led to histopathological and mitochondrial structural abnormalities in the cerebral cortex; reduced GAP-43 and Ng protein expression; induced mitochondrial dysfunction; increased dynamin-related protein1 (Drp1), fission protein1 (Fis1) and mitochondrial fission factor (MFF) expression; and inhibited expression of proteins involved in the p-Drp1 (Ser637) and SIRT1/PGC-1α pathways in neurons. In vitro experiments revealed that silencing PGC-1α or SIRT1 exacerbated the FA-induced mitochondrial fission. However, treatment with Mdivi-1 suppressed mitochondrial fission and alleviated mitochondrial dysfunction caused by FA. These findings reveal that the SIRT1/PGC-1α pathway plays a role in regulating mitochondrial fission and is involved in FA-induced neurotoxicity, highlighting the protective effects of Mdivi-1 against FA-induced neurotoxicity.

Aluminium; Fluorine; Mdivi-1; Mitochondria; SIRT1/PGC-1α.