Mitochondrial Calcium Uniporter (MCU)-Mediated Calcium Overload in Psychoactive Drug Neurotoxicity: From Pathogenesis to Therapeutic Targets.

Abstract

With rapid societal changes and increasing stress levels, the abuse of psychoactive substances has emerged as a global health crisis. Studies indicate that the mitochondrial calcium uniporter (MCU) plays a pivotal role in neurotoxic damage induced by psychoactive substances. As the primary channel for mitochondrial Ca²⁺ uptake, MCU dysfunction can lead to Ca²⁺ overload, oxidative stress, and apoptosis, representing a crucial mechanism underlying neurotoxic damage. Psychoactive substances such as 3,4-Methylenedioxymethamphetamine (MDMA), cocaine, and morphine influence MCU function through multiple pathways, resulting in excessive Ca²⁺ accumulation and mitochondrial dysfunction, ultimately leading to neuronal injury. Although MCU inhibitors have demonstrated potential in alleviating Ca²⁺ overload and improving neural function in preliminary studies, their selectivity and long-term safety require further evaluation. Future research should explore the precise regulatory mechanisms of MCU in neurotoxic damage induced by psychoactive substances and develop more effective targeted therapeutic strategies.

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