Role of the mitochondrial Ca2+ uniporter in Pb2+-induced oxidative stress in human neuroblastoma cells

• Pb2+ induced oxidative stress in SH-SY5Y cells and postnatally exposed rats.
• Oxidative stress induced by Pb2+ is via the mitochondrial Ca2+ uniporter (MCU).
• Mitochondrial Ca2+ uptake in SH-SY5Y cells was inhibited by Pb2+ treatment.
• Overexpression/knockdown of MCU abolished/potentiated the effects of Pb2+.

Lead (Pb2+) has been shown to induce cellular oxidative stress, which is linked to changes in intracellular calcium (Ca2+) concentration. The mitochondrial Ca2+ uniporter (MCU) participates in the maintenance of Ca2+ homeostasis in neurons, but its role in Pb2+-induced oxidative stress is unclear. To address this question, oxidative stress was induced in human neuroblastoma SH-SY5Y cells and in newborn rats by Pb2+ treatment. The results showed that the production of reactive oxygen species is increased in cells upon treatment with Pb2+ in a dose-dependent manner, while glutathione and MCU expression were reduced. Moreover, neuronal nitric oxide synthase protein expression was elevated in rats exposed to Pb2+ during gestation, while MCU expression was decreased. Application of the MCU activator spermine or MCU overexpression reversed Pb2+-induced oxidative stress and inhibition of mitochondrial Ca2+ uptake, while the MCU inhibitor Ru360 and MCU knockdown potentiated the effects of Pb2+. These results indicate that the MCU mediates the Pb2+-induced oxidative stress response in neurons through the regulation of mitochondrial Ca2+ influx.