Sodium arsenite inhibits ALKBH7 increasing tRNA m22G methylation in mitochondrial respiratory chain complex-flankng to drive malignant phenotype of bladder epithelial cells.

Arsenic exposure increases the risk of bladder cancer. The proteomic analysis of arsenic treated bladder epithelial cells revealed significantly upregulated NMES1 expression, which was further validated in the bladder epithelium of arsenite-exposed mice and SV-HUC-1 cells treated with 0.5 μM arsenite. NMES1 is a nuclear-encoded accessory protein of mitochondrial respiratory chain complex IV. A direct interaction between ALKBH7 and NMES1 was confirmed by both molecular docking and protein interaction assays. ALKBH7, a mitochondrial RNA demethylase, was significantly downregulated in arsenic-exposed bladder epithelial cells. Arsenic-mediated ALKBH7 inhibition elevated the m22G methylation level of tRNAs flanking in the mitochondrial respiratory chain, accompanied by decreased mRNA levels of lysine, arginine, and glycine, as well as reduced protein expression of mt-CO2 and mt-ND3, ultimately causing mitochondrial respiratory dysfunction. In addition, arsenic exposure also enhanced cellular glycolysis, which provides energy support for the proliferation and migration of bladder epithelial cells. siNMES1 alleviated arsenic-induced ALKBH7 downregulation and cell malignant phenotype. Overexpressed ALKBH7 effectively attenuated arsenic-enhanced glycolysis and malignant phenotype. In conclusion, arsenic upregulates NMES1 to suppress ALKBH7 expression that increased mt-tRNA m22G methylation modification and reduces the expression of the mt-CO2 and mt-ND3 subunits, thereby impairing mitochondrial respiratory function. Inhibiting ALKBH7 further promoted glycolytic reprogramming to sustain malignant phenotypes in arsenic treated bladder epithelial cells.