Dupuis Luc, Gonzalez de Aguilar Jose-Luis, Oudart Hugues, de Tapia Marc, Barbeito Luis, Loeffler Jean-Philippe
Laboratoire de Signalisations Moléculaires et Neurodégénérescence, U692 INSERM, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France.
Neurodegener Dis. 2004;1(6):245-54. doi: 10.1159/000085063.
Strong evidence shows that mitochondrial dysfunction is involved in amyotrophic lateral sclerosis (ALS), but despite the fact that mitochondria play a central role in excitotoxicity, oxidative stress and apoptosis, the intimate underlying mechanism linking mitochondrial defects to motor neuron degeneration in ALS still remains elusive. Morphological and functional abnormalities occur in mitochondria in ALS patients and related animal models, although their exact nature and extent are controversial. Recent studies postulate that the mislocalization in mitochondria of mutant forms of copper-zinc superoxide dismutase (SOD1), the only well-documented cause of familial ALS, may account for the toxic gain of function of the enzyme, and hence induce motor neuron death. On the other hand, mitochondrial dysfunction in ALS does not seem to be restricted only to motor neurons as it is also present in other tissues, particularly the skeletal muscle. The presence of this 'systemic' defect in energy metabolism associated with the disease is supported in skeletal muscle tissue by impaired mitochondrial respiration and overexpression of uncoupling protein 3. In addition, the lifespan of transgenic mutant SOD1 mice is increased by a highly energetic diet compensating both the metabolic defect and the motorneuronal function. In this review, we will focus on the mitochondrial dysfunction linked to ALS and the cause-and-effect relationships between mitochondria and the pathological mechanisms thought to be involved in the disease.
有力证据表明，线粒体功能障碍与肌萎缩侧索硬化症（ALS）有关，但尽管线粒体在兴奋性毒性、氧化应激和细胞凋亡中起核心作用，将线粒体缺陷与ALS运动神经元变性联系起来的具体潜在机制仍不清楚。ALS患者及相关动物模型的线粒体出现形态和功能异常，尽管其确切性质和程度存在争议。最近的研究推测，家族性ALS唯一有充分文献记载的病因——铜锌超氧化物歧化酶（SOD1）突变形式在线粒体中的错误定位，可能是该酶功能获得性毒性的原因，从而导致运动神经元死亡。另一方面，ALS中的线粒体功能障碍似乎不仅限于运动神经元，因为它也存在于其他组织中，尤其是骨骼肌。骨骼肌组织中线粒体呼吸受损和解偶联蛋白3的过度表达支持了与该疾病相关的这种能量代谢“系统性”缺陷的存在。此外，高能量饮食可延长转基因突变SOD1小鼠的寿命，该饮食既能补偿代谢缺陷，又能改善运动神经元功能。在这篇综述中，我们将重点关注与ALS相关的线粒体功能障碍，以及线粒体与被认为参与该疾病的病理机制之间的因果关系。
