The role of mitochondrial complex III in melatonin-induced ROS production in cultured mesangial cells

Abstract

Melatonin is a potent scavenger of reactive oxygen (ROS) and reactive nitrogen species (RNS). At pharmacological concentrations, however, melatonin is documented to cause ROS/RNS production, especially in cultured cancerous cells. Currently, the mechanism responsible for melatonin‐induced ROS generation remains elusive. In this study, we provided evidence that melatonin, at micromolar concentrations, induced rapid ROS generation by a mitochondrial‐dependent mechanism in primary human mesangial (HM) cells. The melatonin‐induced ROS production occurred independent of changes in Ca²⁺ concentrations in the cytosol and/or in mitochondria. In mitochondria isolated from HM cells and mice kidney tissues, melatonin caused ROS production; this melatonin response was completely blocked by the complex III inhibitor antimycin A. In contrast, both the mitochondrial complex I inhibitor, rotenone, and another complex III inhibitor, myxothiazol, which interacts with complex III at a distinct site, had no significant inhibitory effect on melatonin‐induced ROS generation. These results demonstrate that melatonin induced rapid ROS generation via the antimycin A‐sensitive site of mitochondrial complex III.