Mechanisms of MDMA (Ecstasy)-Induced Oxidative Stress, Mitochondrial Dysfunction, and Organ Damage

MDMA (ecstasy) causes organ damage partly through increased oxidative and nitrosative stress. This review focuses on how oxidative modifications of mitochondrial proteins lead to mitochondrial dysfunction. It describes a method using biotin-N-maleimide as a sensitive probe to identify oxidatively-modified mitochondrial proteins in rats exposed to MDMA, and discusses applications and limitations of this Cys-targeted proteomics approach. The review also covers synergistic drug interactions between MDMA and alcohol, and the potential of this redox-based proteomics method for developing preventive and therapeutic agents against MDMA-induced organ damage.

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Abstract

Despite numerous reports about the acute and sub-chronic toxicities caused by MDMA (3,4-methylenedioxymethamphetamine, ecstasy), the underlying mechanism of organ damage is poorly understood. The aim of this review is to present an update of the mechanistic studies on MDMA-mediated organ damage partly caused by increased oxidative/nitrosative stress. Because of the extensive reviews on MDMA-mediated oxidative stress and tissue damage, we specifically focus on the mechanisms and consequences of oxidative-modifications of mitochondrial proteins, leading to mitochondrial dysfunction. We briefly describe a method to systematically identify oxidatively-modified mitochondrial proteins in control and MDMA-exposed rats by using biotin-N-maleimide (biotin-NM) as a sensitive probe for oxidized proteins. We also describe various applications and advantages of this Cys-targeted proteomics method and alternative approaches to overcome potential limitations of this method in studying oxidized proteins from MDMA-exposed tissues. Finally we discuss the mechanism of synergistic drug-interaction between MDMA and other abused substances including alcohol (ethanol) as well as application of this redox-based proteomics method in translational studies for developing effective preventive and therapeutic agents against MDMA-induced organ damage.