Mitochondrial calcium overload is the trigger for carbon monoxide neurotoxicity
Abstract
Abstract Carbon monoxide is an important gasotransmitter and regulator of cell function in different tissues, including the central nervous system. However, in large doses, it is a poisonous gas that causes mortality and morbidity. Moreover, the majority of survivors of high-dose exposures develop serious neurological conditions. Here, we studied the effect of toxic concentrations of carbon monoxide released from the compound CORM-401 and its removal (re-oxygenation) on calcium signalling in primary cortical neurons and astrocytes. We found that CO induces changes in intracellular Ca 2+ concentration in both neurons and astrocytes. The mechanism of these signals was different—in neurons, it was activated by NMDA and AMPA receptors, while in astrocytes, CO-induced fusion of VNUT2-positive vesicles followed by activation of P2Y receptors. Calcium signal in neurons and astrocytes promotes mitochondrial calcium uptake, which dramatically increases after the removal of CO from the medium, which, in combination with higher rates of production of ROS, induces mitochondrial permeability transition and cell death. CO-induced death of neurons and astrocytes could be prevented with partial inhibition of mitochondrial calcium uptake by Tg2112x and/or inhibition of ROS production in the phase of re-oxygenation. Thus, the bidirectional interaction between mitochondrial calcium overload and production of reactive oxygen species is crucial for CO-induced death of neurons and astrocytes.