Study of ATF4/CHOP axis-mediated mitochondrial unfolded protein response in neuronal apoptosis induced by methylmercury

Methylmercury (MeHg) is a widely distributed environmental pollutant that can easily cross the blood-brain barrier and accumulate in the brain, thereby damaging the central nervous system. Studies have shown that MeHg-induced mitochondrial damage and apoptosis play a crucial role in its neurotoxic effects. Mitochondrial unfolded protein response (UPR^mt) is indispensable to maintain mitochondrial protein homeostasis and ensure mitochondrial function, and the ATF4/CHOP axis is one of the signaling pathways to activate UPR^mt. In this study, the role of the ATF4/CHOP axis-mediated UPR^mt in the neurotoxicity of MeHg has been investigated by C57BL/6 mice and the HT22 cell line. We discovered that mice exposed to MeHg had abnormal neurobehavioral patterns. The pathological section showed a significant decrease in the number of neurons. MeHg also resulted in a reduction in mtDNA copy number and mitochondrial membrane potential (MMP). Additionally, the ATF4/CHOP axis and UPR^mt were found to be significantly activated. Subsequently, we used siRNA to knock down ATF4 or CHOP and observed that the expression of UPR^mt-related proteins and the apoptosis rate were significantly reduced. Our research showed that exposure to MeHg can over-activate the UPR^mt through the ATF4/CHOP axis, leading to mitochondrial damage and ultimately inducing neuronal apoptosis.