Stable Over-expression of the 2-oxoglutarate Carrier Enhances Neuronal Cell Resistance to Oxidative Stress via Bcl-2-dependent Mitochondrial GSH Transport

Publication Date

3-7-2014

Document Type

Article

Organizational Units

College of Natural Science and Mathematics, Biological Sciences

Keywords

2‐oxoglutarate carrier, Bcl‐2, Glutathione, Mitochondria, Nitrosative stress, Oxidative stress

Abstract

Mitochondrial glutathione (GSH) is a key endogenous antioxidant and its maintenance is critical for cell survival. Here, we generated stable NSC34 motor neuron‐like cell lines over‐expressing the mitochondrial GSH transporter, the 2‐oxoglutarate carrier (OGC), to further elucidate the importance of mitochondrial GSH transport in determining neuronal resistance to oxidative stress. Two stable OGC cell lines displayed specific increases in mitochondrial GSH content and resistance to oxidative and nitrosative stressors, but not staurosporine. Inhibition of transport through OGC reduced levels of mitochondrial GSH and resensitized the stable cell lines to oxidative stress. The stable OGC cell lines displayed significant up‐regulation of the anti‐apoptotic protein, B cell lymphoma 2 (Bcl‐2). This result was reproduced in parental NSC34 cells by chronic treatment with GSH monoethylester, which specifically increased mitochondrial GSH levels. Knockdown of Bcl‐2 expression decreased mitochondrial GSH and resensitized the stable OGC cells to oxidative stress. Finally, endogenous OGC was co‐immunoprecipitated with Bcl‐2 from rat brain lysates in a GSH‐dependent manner. These data are the first to show that increased mitochondrial GSH transport is sufficient to enhance neuronal resistance to oxidative stress. Moreover, sustained and specific enhancement of mitochondrial GSH leads to increased Bcl‐2 expression, a required mechanism for the maintenance of increased mitochondrial GSH levels.

Copyright Date

3-7-2014

Copyright Statement / License for Reuse

All Rights Reserved
All Rights Reserved.

Rights Holder

International Society for Neurochemistry

Provenance

Received from author

Language

English (eng)

Extent

12 pgs

Publication Statement

Copyright is held by the International Society for Neurochemistry. User is responsible for all copyright compliance.

Publication Title

Journal of Neurochemistry

Volume

130

Issue

1

First Page

75

Last Page

86

ISSN

1471-4159

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