Hypoxia causes mitochondrial translocation to the perinuclear region in pulmonary artery endothelial cells (PAECs): Implications for signal transduction

Abstract

Previous reports indicate that hypoxia causes mitochondrial reactive oxygen species (ROS) generation and nuclear oxidant stress, both of which seem to be involved in signal transduction. In this study, we tested the idea that a microtubule-based motor system causes mitochondrial translocation to the perinuclear region in hypoxic PAECs that is required for oxidative DNA modifications. Using confocal microscopy in Mitotracker-stained PAECs, we found that within two hours of hypoxic exposure, mitochondria that were initially distributed diffusely throughout the cytosol had clustered in close proximity to the nuclear membrane. The perinuclear mitochondrial clustering was suppressed by the microtubule inhibitor nocodazole and potentiated when centripetal mitochondrial movement was blocked by over-expression of a dominant-negative kinesin mutant. While nocodazole failed to suppress hypoxia-induced ROS generation, inhibition of perinuclear mitochondrial clustering prevented the nuclear oxidant stress, detected as oxidative base modifications in the promoter of the VEGF gene. Collectively, these findings suggest that hypoxia initiates the vectorial movement of mitochondria to the vicinity of the nucleus, which serves to create a ROS-enriched micro-domain important for signaling.