Proteomic analysis of rat brain mitochondria following exposure to dopamine quinone: Implications for Parkinson disease

Abstract

Oxidative stress and mitochondrial dysfunction have been linked to dopaminergic neuron degeneration in Parkinson disease. We have previously shown that dopamine oxidation leads to selective dopaminergic terminal degeneration in vivo and alters mitochondrial function in vitro. In this study, we utilized 2-D difference in-gel electrophoresis to assess changes in the mitochondrial proteome following in vitro exposure to reactive dopamine quinone. A subset of proteins exhibit decreased fluorescence labeling following dopamine oxidation, suggesting a rapid loss of specific proteins. Amongst these proteins are mitochondrial creatine kinase, mitofilin, mortalin, the 75 kDa subunit of NADH dehydrogenase, and superoxide dismutase 2. Western blot analyses for mitochondrial creatine kinase and mitofilin confirmed significant losses in isolated brain mitochondria exposed to dopamine quinone and PC12 cells exposed to dopamine. These results suggest that specific mitochondrial proteins are uniquely susceptible to changes in abundance following dopamine oxidation, and carry implications for mitochondrial stability in Parkinson disease neurodegeneration.

Bioactive l-DOPA induced quinoprotein formation to inhibit root growth of cucumber seedlings

“…12,26,27) Recent proteomics studies using radiolabeled dopamine showed that dopaminequinone covalently modified critical proteins such as mitochondrial chaperonin, ubiquinol-cytochrome c reductase, mortalin, mitofilin, creatine kinase, and NADH dehydrogenase in animal and human cells. 28,29) The covalent modification of these proteins by dopaminequinone may contribute to cytotoxicity. 12,15) l-DOPA itself is not toxic; only oxidation products of l-DOPA such as reactive oxygen species and reactive quinones are phytotoxic.…”

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…This implication suggests that OS-mediated mitochondrial dysfunction may be responsible, at least partially, for neurodegeneration in the brains of A30P (-synuclein transgenic mice. However, a proteomic analysis showed that dopamine quinone, an oxidized and damaging form of dopamine, could alter brain mitochondria, with implications for PD (388).…”

Mitochondrial proteomics as a selective tool for unraveling Parkinson’s disease pathogenesis

“…The study also detected decreased abundancy of mortalin, a mitochondrial inner membrane-associated chaperone protein [155] important for importing and folding mitochondrial proteins [162], following DAQ exposure. Mitofilin also showed decreased fluorescence labeling in animals exposed to DAQ, compared with non-exposed control animals.…”

“…As an unbiased approach to identify mitochondrial proteins susceptible to DA oxidation, isolated rat brain mitochondria exposed to reactive DAQ were exposed to 2-DE-DIGE combined with cysteine-and lysine-reactive fluorescent dyes [155]. Detection of the loss of specific mitochondrial proteins, encompassing a range of mitochondrial functions, including structural maintenance, transport and metabolism, was reported.…”