Mitochondrial redox-driven mitofusin 2 S-glutathionylation promotes neuronal necroptosis via disrupting ER-mitochondria crosstalk in cadmium-induced neurotoxicity

Abstract Reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and mitochondrial dysfunction are known to affect the structural and functional damage in the neural system. Cadmium (Cd) is an environmental contaminant that is widely found in numerous environmental matrices and exhibits potential neurotoxic risk. However, it remains unclear how mitochondrial redox status induces and whether Cd destabilizes the ER-mitochondrial crosstalk to have a toxic effect on the neural system. Herein, in our current study the bioinformatics analysis revealed the important role of protein interaction, mitochondrion machinery in brain sample from Alzheimer's disease (AD) patients. Further, we established neurotoxicity model in vivo and in vitro induced by cadmium chloride (CdCl2). We demonstrated that CdCl2 exposure disrupts the balance of mitochondrial redox represented by an enhanced mitoROS level, which enhances mitofusin 2 (Mfn2) S-glutathionylation and disrupts the mitochondria-associated ER membranes (MAMs) for crosstalk between the ER and mitochondria to exacerbate neuronal necroptosis. Mechanistically, it was shown that CdCl2 exposure significantly enhances the mitochondria-associated degradation (MAD) of Mfn2 via S-glutathionylation, which inhibits Mfn2 localization to the MAMs and subsequently leads to the formation of the RIPK1-RIPK3-p-MLKL complex (as key component of the necrosome) at MAMs, to promote neuronal necroptosis. Furthermore, the glutaredoxin 1 (Grx1) catalyzed and Mfn2 overexpression restored S-glu-Mfn2, MAMs perturbation, necrosome formation and necroptosis in neuron induced by CdCl2 exposure in vitro. Moreover, the intervention of mitochondrial redox with antioxidants, such as N-acetyl-L-cysteine (NAC) and mitochondria-targeted antioxidant Mito-TEMPO, remodulated the S-glutathionylation of Mfn2 involved in the antagonism of CdCl2-induced necroptosis and neurotoxicity in vivo and in vitro. Taken together, our results were the first time to demonstrate that S-glutathionylation of Mfn2 promote neuronal necroptosis via disrupting ER-mitochondrial crosstalk in CdCl2-induced neurotoxicity, providing the novel mechanistic insight into how hazardous chemicals-induced adverse effects in various organs and tissues could be interpreted by intraorganelle pathways under the control of MAMs components in neurons.