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Author Notes:

Address correspondence to: Zixu Mao, Department of Pharmacology, Emory University, 615 Michael Street, Atlanta, Georgia 30322, USA. Phone: 404.712.8581; Fax: 404.727.3728; E-mail: zmao@pharm.emory.edu.

We thank Pier Giorgio Mastroberardino for help with mitochondria purification, Hoon Ryu for pDsRed2-Mito plasmid, Howard Rees for help with confocal microscopy, James Greene for critical reading of the manuscript, Megan Dautherty for assistance with immunocytochemistry, Yingjie Li and Minzheng Wang for animal studies, and Jean-Francois Pare and Hong Yi for assistance with electron microscopy.

The authors have declared that no conflict of interest exists.

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Research Funding:

This work was partially supported by NIH grants ES015317, AG023695, and NS048254 (to Z. Mao) and ES016731 (to G. Miller and Z. Mao), The Robert W. Woodruff Health Sciences Center Fund (to Z. Mao), Michael J. Fox Foundation (to Z. Mao), and Viral Vector, Tissue Bank, and Imaging Cores of the Emory Neuroscience NINDS Core Facilities grant P30NS055077.

Direct regulation of complex I by mitochondrial MEF2D is disrupted in a mouse model of Parkinson disease and in human patients

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Journal Title:

Journal of Clinical Investigation

Volume:

Volume 121, Number 3

Publisher:

, Pages 930-940

Type of Work:

Article | Final Publisher PDF

Abstract:

The transcription factors in the myocyte enhancer factor 2 (MEF2) family play important roles in cell survival by regulating nuclear gene expression. Here, we report that MEF2D is present in rodent neuronal mitochondria, where it can regulate the expression of a gene encoded within mitochondrial DNA (mtDNA). Immunocytochemical, immunoelectron microscopic, and biochemical analyses of rodent neuronal cells showed that a portion of MEF2D was targeted to mitochondria via an N-terminal motif and the chaperone protein mitochondrial heat shock protein 70 (mtHsp70). MEF2D bound to a MEF2 consensus site in the region of the mtDNA that contained the gene NADH dehydrogenase 6 (ND6), which encodes an essential component of the complex I enzyme of the oxidative phosphorylation system; MEF2D binding induced ND6 transcription. Blocking MEF2D function specifically in mitochondria decreased complex I activity, increased cellular H2O2 level, reduced ATP production, and sensitized neurons to stress-induced death. Toxins known to affect complex I preferentially disrupted MEF2D function in a mouse model of Parkinson disease (PD). In addition, mitochondrial MEF2D and ND6 levels were decreased in postmortem brain samples of patients with PD compared with age-matched controls. Thus, direct regulation of complex I by mitochondrial MEF2D underlies its neuroprotective effects, and dysregulation of this pathway may contribute to PD.

Copyright information:

© 2011, American Society for Clinical Investigation

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