Arsenite methyltransferase 3 is required for mitochondrial function and hepatic lipid metabolism

Arsenic poisoning has severe health effects, and accordingly, most research on the arsenite methyltransferase 3 (AS3MT) enzyme has focused on its role in arsenic metabolism, overlooking potential endogenous functions. We discovered an arsenic-independent role for AS3MT in regulating hepatic energy metabolism. as3mt loss in zebrafish caused differential expression of thousands of genes in the liver, with many of the downregulated genes playing roles in mitochondrial energy metabolism. Similar genes were downregulated in AS3MT-depleted human cells. as3mt zebrafish mutants had large, malformed mitochondria, were more sensitive to both arsenic and the mitochondrial toxin rotenone, and impaired swimming velocity. as3mt mutants developed steatosis, a hallmark of mitochondrial dysfunction. Restoring As3mt in hepatocytes of as3mt mutants rescued steatosis and mitochondrial gene expression. Overexpression of As3mt in wild-type hepatocytes protected against steatosis caused by iAs induced. This demonstrates a novel, conserved, endogenous role for As3mt in hepatic energy metabolism, identifies As3mt loss as a previously unrecognized cause of steatosis, and suggests that arsenic may induce mitochondrial dysfunction due to sequestering As3mt from its endogenous role.