Cadmium disrupts mitochondrial distribution and activates excessive mitochondrial fission by elevating cytosolic calcium independent of MCU-mediated mitochondrial calcium uptake in its neurotoxicity

Abstract

Cadmium (Cd) is a ubiquitous environmental and occupational pollutant that is considered as a high-risk factor for neurodegenerative diseases. However, the mechanism underlying Cd-induced neurotoxicity has not been fully elucidated. Abnormal mitochondrial distribution and excessive mitochondrial fission are increasingly implicated in various neurological pathologies. Herein, by exposing primary cortical neurons to Cd (10 and 100 μM) for various times (0, 6, 12, and 24 h), we observed that the rapid motility of the mitochondria in neurons progressively slowed. Many more mitochondria were transported and distributed to the somas of Cd-treated neurons. Coupled with abnormal mitochondrial distribution, Cd exposure triggered excessive mitochondrial fragmentation, followed by mitochondrial membrane potential loss and neuronal damage. However, BAPTA-AM, a chelator of cytosolic calcium ([Ca2+]c), significantly attenuated Cd-induced abnormal mitochondrial distribution and excessive mitochondrial fission, which protected against Cd-induced mitochondrial damage and neuronal toxicity. In contrast to the increase in [Ca2+]c, Cd exposure had no effect on the level of mitochondrial calcium ([Ca2+]m). Inhibiting [Ca2+]m uptake, either by ruthenium 360 (Ru360) or by knock-out of mitochondrial calcium uniporter (MCU), failed to alleviate Cd-induced mitochondrial damage and neuronal toxicity. Additionally, in MCU knock-out neurons, BAPTA-AM effectively prevented Cd-induced abnormal mitochondrial distribution and excessive mitochondrial fission. Taken together, Cd exposure disrupts mitochondrial distribution and activates excessive mitochondrial fission by elevating [Ca2+]c independent of MCU-mediated mitochondrial calcium uptake, thereby leading to neurotoxicity. Chelating overloaded [Ca2+]c is a promising strategy to prevent the neurotoxicity of Cd.