Mitochondrial abnormalities in spinal and bulbar muscular atrophy
Mitochondrial abnormalities in spinal and bulbar muscular atrophy
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DOI：
10.1093/hmg/ddn310
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发表时间：
2009-01-01
影响因子：
3.5
通讯作者：
Fischbeck, Kenneth H.
中科院分区：
文献类型：
--
作者：
Ranganathan, Srikanth;Harmison, George G.;Fischbeck, Kenneth H.
脊髓和球性肌萎缩症（SBMA）是一种由雄激素受体（AR）中聚谷氨酰胺扩增突变引起的运动神经元疾病。我们研究了突变蛋白是否会改变线粒体功能。我们发现，在MN-1和PC12细胞中，组成型和强力霉素诱导的AR突变体的表达分别与线粒体膜的去极化有关。环孢素A抑制线粒体通透性过渡孔的打开，减轻了这种情况。我们还发现，在配体存在的情况下，突变蛋白的表达导致活性氧水平升高，这被抗氧化剂辅酶Q10和伊地苯酮处理阻断。MN-1细胞中的突变蛋白也导致Bax、caspase 9和caspase 3的升高。我们评估了突变AR对线粒体蛋白转录的影响，并发现SBMA敲入小鼠受影响组织中过氧化物酶体增殖体激活受体γ辅助激活因子1和线粒体特异性抗氧化剂超氧化物歧化酶2的表达发生改变。此外，我们发现AR与培养细胞中的线粒体有关。因此，本研究为SBMA细胞和动物模型中的线粒体功能障碍提供了证据，无论是通过对核编码线粒体基因转录的间接影响，还是通过突变蛋白对线粒体的直接影响，或两者兼而有之。这些发现表明线粒体治疗SBMA可能有益。
Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by polyglutamine expansion mutation in the androgen receptor (AR). We investigated whether the mutant protein alters mitochondrial function. We found that constitutive and doxycycline-induced expression of the mutant AR in MN-1 and PC12 cells, respectively, are associated with depolarization of the mitochondrial membrane. This was mitigated by cyclosporine A, which inhibits opening of the mitochondrial permeability transition pore. We also found that the expression of the mutant protein in the presence of ligand results in an elevated level of reactive oxygen species, which is blocked by the treatment with the antioxidants co-enzyme Q10 and idebenone. The mutant protein in MN-1 cells also resulted in increased Bax, caspase 9 and caspase 3. We assessed the effects of mutant AR on the transcription of mitochondrial proteins and found altered expression of the peroxisome proliferator-activated receptor gamma coactivator 1 and the mitochondrial specific antioxidant superoxide dismutase-2 in affected tissues of SBMA knock-in mice. In addition, we found that the AR associates with mitochondria in cultured cells. This study thus provides evidence for mitochondrial dysfunction in SBMA cell and animal models, either through indirect effects on the transcription of nuclear-encoded mitochondrial genes or through direct effects of the mutant protein on mitochondria or both. These findings indicate possible benefit from mitochondrial therapy for SBMA.