Melatonin alleviates fluoride-induced developmental neurotoxicity by restoring SIRT3/HIF-1α axis-mediated mitochondrial dysfunction and reversing energy metabolism reprogramming

Excessive fluoride exposure causes developmental neurotoxicity, but the mechanism linking fluoride to neuronal energy metabolism disorders-especially via mitochondrial function-remains elusive. Here, we investigated whether the SIRT3/HIF-1α axis mediates fluoride-induced developmental neurotoxicity and if melatonin (Mel) mitigates this by targeting energy metabolism. In vivo, Sprague-Dawley rats were perinatally exposed to sodium fluoride (NaF: 10, 20, 40 mg/kg/day) with/without Mel (10 mg/kg/day); in vitro, HT22 cells were treated with NaF (0, 20, 40, 60 mg/L) and/or Mel (20 μmol/L), or transfected with HIF-1α siRNA. Results demonstrated that NaF suppressed SIRT3 expression, resulting in mitochondrial dysfunction and reactive oxygen species (ROS) accumulation. Elevated ROS upregulated HIF-1α, shifting cellular energy metabolism from oxidative phosphorylation (OXPHOS) toward glycolysis. This metabolic reprogramming was evidenced by decreased oxygen consumption rate (OCR) and NDUFS1 expression, alongside increased extracellular acidification rate (ECAR), upregulation of PFKFB3, PKM2, and LDHA, and elevated pyruvate and lactate levels. These changes ultimately led to reduced ATP production and cognitive impairment in offspring rats. Notably, Mel attenuated NaF-induced mitochondrial dysfunction by upregulating SIRT3 and inhibiting HIF-1α, thereby restoring OXPHOS and increasing ATP levels. Furthermore, HIF-1α silencing similarly reversed NaF-induced disruptions in energy metabolism. Our findings reveal a novel mechanism for NaF-induced developmental neurotoxicity and highlight the potential of Mel as a protective agent against environmental fluoride exposure.