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Direct regulation of complex I by mitochondrial MEF2D is disrupted in a mouse model of Parkinson disease and in human patients
Hua She, … , Claudia Testa, Zixu Mao
Hua She, … , Claudia Testa, Zixu Mao
Published February 14, 2011
Citation Information: J Clin Invest. 2011;121(3):930-940. https://doi.org/10.1172/JCI43871.
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Research Article Neuroscience

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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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.

Authors

Hua She, Qian Yang, Kennie Shepherd, Yoland Smith, Gary Miller, Claudia Testa, Zixu Mao

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Figure 2

Specific sequence and chaperone protein required for localization of MEF2D to mitochondria.

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Specific sequence and chaperone protein required for localization of MEF...
(A) Lack of mitochondrial localization by ΔN30MEF2D. Western blotting showed the presence of overexpressed ΔN30MEF2D in cytoplasmic and nuclear fractions, but not in the mitochondrial fraction, of SN4741 cells (n = 3). VDAC, PARP, and c-Raf are mitochondrial, nuclear, and cytoplasmic markers, respectively. Control indicates the control vector group. (B) Immunocytochemistry analysis of mitochondrial localization of transfected MEF2D-Flag. Overexpressed ΔN30MEF2D did not colocalize with MitoTracker in SN4741 cells (n = 50 cells; **P < 0.01). Experiments were repeated 4 times. Scale bars: 15 μm. (C and D) Requirement of mtHsp70 for mitochondrial targeting of MEF2D (n = 4; **P < 0.01). Control indicates untreated. Knocking down mouse mtHsp70 by siRNA reduced MEF2D level in purified mitochondria from SN4741 cells (C). Knocking down mouse mtHsp70 by siRNA did not reduce whole cell MEF2D level in SN4741 cells (D). MnSOD is a known mtHsp70-imported mitochondrial matrix protein.

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