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

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 6

Inhibition of mitochondrial MEF2D by toxic signals relevant to PD.

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Inhibition of mitochondrial MEF2D by toxic signals relevant to PD. (A) R...
(A) Reduced binding of MEF2D to ND6 after neurotoxin treatment. SN4741 cells were treated with MPP+ (25 μM) or rotenone (Rot, 100 nM) for 12 hours. ChIP assay showed that binding of MEF2D to ND6 was greatly reduced (n = 4; **P < 0.01). Control indicates untreated. (B) Reduced mitochondrial MEF2D and ND6 protein levels after neurotoxin treatment. Western blotting showed that levels of MEF2D and ND6 in purified mitochondria, but not in nuclei, were significantly reduced (n = 4; **P < 0.01). Control indicates untreated. (C) Immunocytochemical analysis of mitochondrial MEF2D after MPP+ and rotenone treatment. MPP+ and rotenone preferentially reduced colocalization of MEF2D with MitoTracker (n = 50 cells; **P < 0.01). Scale bars: 10 μm. Experiments were repeated 4 times. Control indicates untreated. (D) Effect of mitochondrial MEF2D-ND6 pathway on MPP+ toxicity in SN4741 cells. SN4741 cells were treated with MPP+ after infection with the control or with Mt2Ddn, Mt2DVP16, or MtND6 lentiviruses. Treatment was either with different doses for 24 hours (top) or the 5-μM dose for different times (bottom). Cell viability was measured by WST-1 assay (n = 4; *P < 0.05; **P < 0.01). Control indicates the control vector group.