Microcystin-leucine-arginine Induced Neurotoxicity By Initiating Mitochondrial Fission In Hippocampal Neurons

Microcystins（MCs）are monocyclic heptapeptide environmental toxins produced by cyanobacteria.MC-LR is the most toxic,widely distributed and most studied among its many isomers.MC-LR can cross the blood-brain barrier（BBB）and have potent acute hippocampal neurotoxicity.Chronic exposure to MC-LR has been confirmed to cause learning and memory deficits in mice,but the potential molecular mechanism of MC-LR-caused neurotoxicity is still unclear.The hippocampus plays a very important role in the formation of learning and memory abilities.As a high-energy-consuming cell,neurons in the hippocampus can normally perform physiological functions depending on the role of the mitochondria,the energy metabolism center in the cell.In cells,mitochondria are constantly changing,and the dynamic balance of mitochondria plays an important role in maintaining the normal shape and function of mitochondria.Existing data indicate that mitochondria are one of the target organelles for the action of MC-LR.Therefore,we further explored the effect of MC-LR on the dynamic changes of mitochondria and explored the molecular mechanism of MC-LR leading to neurodegenerative changes by affecting mitochondrial dynamics.In this research,we observed that MC-LR induced oxidative stress,mitochondrial fission and apoptosis in HT-22 hippocampal neurons.Moreover,we observed that MC-LR induced mitochondrial fragmentation via activating Dynamin-related protein 1（Drp1）and Mitochondrial fission factor（Mff）,bringing about apoptosis of hippocampal neuronal cells.The observed effects were associated with increasing intracellular Ca²⁺and reducing activity of protein phosphatases 2A（PP2A）as results of MC-LR exposure in HT-22 cells.Ca²⁺activates Ca MKⅡand Akt to enhance phosphorylation of Drp1 at Ser616 residue.Inhibition of PP2A activity increased AMPK activity to mediate phosphorylation of Mff.Our data proved that MC-LR can cause mitochondrial fragmentation and apoptosis in hippocampal neurons,which provides novel perception to explore the mechanism related to MC-LR-induced neurotoxicity and Alzheimer’s disease-like changes.