Arsenic promotes MIN6 cells dysfunction via ACO2-αKG-mitophagy pathway

Arsenite can impair pancreatic β-cell function, but the mechanisms linking mitochondrial metabolic disturbances to this toxicity remain incompletely understood. Therefore, mitophagy, which removes dysfunctional mitochondria by lysosomal degradation, has attracted much attention. Mitochondrial (cis)aconitase 2 (ACO2) is a critical enzyme in the tricarboxylic acid cycle responsible for coordinating mitochondrial functions and is involved in energy metabolism. However, the role of ACO2 in arsenite-induced mitochondrial dysfunction and altered mitophagy in pancreatic β cells remains unclear. In this study, we demonstrated that arsenic exposure leads to the downregulation of mitochondrial ACO2. As expected, ACO2 overexpression reversed the arsenic-induced MIN6 cells dysfunction. In addition, arsenic induced the inhibition of mitophagy in islets β-cells characteristic with the downregulation of PTEN-induced putative kinase 1 (PINK1) , Parkin RBR E3 ubiquitin protein ligase (Parkin) and sequestosome 1 (p62/SQSTM1), accompanied by an increased level of microtubule-associated protein 1 light chain 3-II (LC3-II). ACO2 reversed these alterations in protein expression. Simultaneously, ACO2 overexpression elevated adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) levels, decreased mitochondrial reactive oxygen species (mtROS) production, and alleviated the functional impairment of β-cells induced by arsenic. Moreover, supplementation with α-ketoglutarate (α-KG), a downstream metabolite of ACO2, similarly mitigated arsenic-induced mitophagy inhibition and functional impairment of MIN6 cells. In conclusion, this study identified a novel mechanism by which inorganic arsenic can lead to pancreatic β cell dysfunction via the ACO2-αKG-mitophagy pathway. These findings advance the mechanistic understanding of arsenite-induced β-cell toxicity.