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 7

Correlation of mitochondrial MEF2D in a MPTP model of PD and in postmortem brains of PD patients.

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Correlation of mitochondrial MEF2D in a MPTP model of PD and in postmort...
(A) Reduced mitochondrial MEF2D and ND6 levels in the brains of MPTP-treated mice (n = 18; **P < 0.01). Mitochondria purified from brain SNpc region were analyzed by Western blotting. Experiments were repeated 3 times. (B) Role of mitochondrial MEF2D-ND6 pathway in maintaining TH+ neurons in SNpc in a MPTP mouse model of PD. For each group, 3 mice received stereotactic injection of control vector (GFP) or Mt2Ddn lentivirus in SN. 2 weeks later, mice were exposed to MPTP. After treatment for 7 days, survival of lentivirus-transduced TH+ neurons in SN was determined by immunohistochemistry. Scale bars: 30 μm. Quantitative analysis of 9 mice from 3 independent experiments is also shown (**P < 0.01). (C) Reduced mitochondrial MEF2D and ND6 levels in the brains of human PD patients. Mitochondria were purified from brain striata of postmortem PD patients and normal controls. Equal amounts of mitochondrial proteins were subjected to Western blotting. Quantitative analysis of the bands is also shown (n = 13 patients and 13 controls; *P < 0.01). Experiments were repeated 2 times.