Dopamine and Methamphetamine Differentially Affect Electron Transport Chain Complexes and Parkin in Rat Striatum: New Insight into Methamphetamine Neurotoxicity.

Bernard Schneider,Heli Chauhan,Anna Moszczynska,Akhil Sharma,Viktoriia Bazylianska

doi:10.3390/ijms23010363

Abstract

Methamphetamine (METH) is a highly abused psychostimulant that is neurotoxic to dopaminergic (DAergic) nerve terminals in the striatum and increases the risk of developing Parkinson’s disease (PD). In vivo, METH-mediated DA release, followed by DA-mediated oxidative stress and mitochondrial dysfunction in pre- and postsynaptic neurons, mediates METH neurotoxicity. METH-triggered oxidative stress damages parkin, a neuroprotective protein involved in PD etiology via its involvement in the maintenance of mitochondria. It is not known whether METH itself contributes to mitochondrial dysfunction and whether parkin regulates complex I, an enzymatic complex downregulated in PD. To determine this, we separately assessed the effects of METH or DA alone on electron transport chain (ETC) complexes and the protein parkin in isolated striatal mitochondria. We show that METH decreases the levels of selected complex I, II, and III subunits (NDUFS3, SDHA, and UQCRC2, respectively), whereas DA decreases the levels only of the NDUFS3 subunit in our preparations. We also show that the selected subunits are not decreased in synaptosomal mitochondria under similar experimental conditions. Finally, we found that parkin overexpression does not influence the levels of the NDUFS3 subunit in rat striatum. The presented results indicate that METH itself is a factor promoting dysfunction of striatal mitochondria; therefore, it is a potential drug target against METH neurotoxicity. The observed decreases in ETC complex subunits suggest that DA and METH decrease activities of the ETC complexes via oxidative damage to their subunits and that synaptosomal mitochondria may be somewhat “resistant” to DA- and METH-induced disruption in mitochondrial ETC complexes than perikaryal mitochondria. The results also suggest that parkin does not regulate NDUFS3 turnover in rat striatum.

Highlights

Introduction published maps and institutional affilMethamphetamine (METH) is a central nervous system (CNS) psychostimulant with a high potential for abuse
We provide in vitro evidence that METH alone can decrease the levels of a few striatal mitochondrial protein subunits, including NDUFS3 of complex I, and that the selected
To investigate how increasing concentrations of DA affect the levels of striatal mitochondrial electron transport chain (ETC) complexes, cytoplasm-suspended mitochondria were treated with 0–50 mM DA for 30 min at 37 ◦ C

Summary

Introduction

Methamphetamine (METH) is a central nervous system (CNS) psychostimulant with a high potential for abuse. METH abuse is a serious public health problem in the US and worldwide. In the US, over 1.2 million people currently use METH [1]. There is no effective FDA-approved pharmacotherapy for METH addiction or preventive measures against toxicity of this drug to the brain [2]. Chronic METH use, at high doses, can have severe physical and psychological consequences, including cognitive impairments and psychotic symptoms [3], which are the manifestations of this neurotoxicity. High doses of METH are neurotoxic to the dorsal striatum where the drug induces dopaminergic (DAergic) deficits and increases the risk of developing

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