ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes.
ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes.
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DOI：
10.1186/1471-2202-4-16
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发表时间：
2003-07-15
期刊：
影响因子：
2.4
通讯作者：
Xu Z
中科院分区：
文献类型：
--
作者：
Higgins CM;Jung C;Xu Z
肌萎缩侧索硬化症（ALS）是一种年龄依赖性神经退行性疾病，可导致运动神经元变性、瘫痪和死亡。Cu，Zn超氧化物歧化酶（SOD 1）的突变是该疾病家族形式的一个原因。表达突变SOD 1的转基因小鼠发生与人类相似的年龄依赖性运动神经元变性、骨骼肌无力、瘫痪和死亡。突变SOD 1诱导运动神经元变性的机制尚不清楚，但在运动神经元变性的早期阶段已观察到广泛的线粒体空泡化。这种空泡化是如何发展的尚不清楚，但可能涉及自噬空泡化、线粒体通透性转换（MPT）或未表征的机制。为了确定这些可能性是真实的，我们详细研究了表达突变体SOD1G93A的转基因小鼠的空泡模式。电子显微镜（EM）显示的泡状结构表明，空泡起源于线粒体膜间隙的扩张和线粒体外膜的延伸。免疫荧光显微镜和免疫金电子显微镜显示，空泡由SOD 1和线粒体外膜标记物界定，但线粒体内膜标记物位于空泡内的焦点区域。小的液泡含有细胞色素c，而大的液泡是多孔的，缺乏细胞色素c。胆固醇缺乏溶酶体信号，但含有丰富的过氧化物酶体和SOD 1聚集体。这些发现表明，突变体SOD 1，可能通过与其聚集相关的毒性，通过诱导线粒体外膜的延伸和渗漏以及膜间隙的扩张引起线粒体变性。这可以释放通常驻留在膜间隙中的促细胞死亡分子并引发运动神经元变性。这种通过膜间空间扩张（MVISE）的线粒体空泡化既不符合MPT也不符合自噬空泡化机制，因此是哺乳动物CNS中线粒体变性的先前未表征的机制。
Amyotrophic lateral sclerosis (ALS) is an age-dependent neurodegenerative disease that causes motor neuron degeneration, paralysis and death. Mutations in Cu, Zn superoxide dismutase (SOD1) are one cause for the familial form of this disease. Transgenic mice expressing mutant SOD1 develop age-dependent motor neuron degeneration, skeletal muscle weakness, paralysis and death similar to humans. The mechanism whereby mutant SOD1 induces motor neuron degeneration is not understood but widespread mitochondrial vacuolation has been observed during early phases of motor neuron degeneration. How this vacuolation develops is not clear, but could involve autophagic vacuolation, mitochondrial permeability transition (MPT) or uncharacterized mechanisms. To determine which of these possibilities are true, we examined the vacuolar patterns in detail in transgenic mice expressing mutant SOD1G93A. Vacuolar patterns revealed by electron microscopy (EM) suggest that vacuoles originate from the expansion of the mitochondrial intermembrane space and extension of the outer mitochondrial membrane. Immunofluorescence microscopy and immuno-gold electron microscopy reveal that vacuoles are bounded by SOD1 and mitochondrial outer membrane markers, but the inner mitochondrial membrane marker is located in focal areas inside the vacuoles. Small vacuoles contain cytochrome c while large vacuoles are porous and lack cytochrome c. Vacuoles lack lysosomal signal but contain abundant peroxisomes and SOD1 aggregates. These findings demonstrate that mutant SOD1, possibly by toxicity associated with its aggregation, causes mitochondrial degeneration by inducing extension and leakage of the outer mitochondrial membrane, and expansion of the intermembrane space. This could release the pro-cell death molecules normally residing in the intermembrane space and initiate motor neuron degeneration. This Mitochondrial Vacuolation by Intermembrane Space Expansion (MVISE) fits neither MPT nor autophagic vacuolation mechanisms, and thus, is a previously uncharacterized mechanism of mitochondrial degeneration in mammalian CNS.
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DOI：
10.1097/00005072-199705000-00008
发表时间：
1997-05-01
影响因子：
3.2
作者：
Durham, HD;Roy, J;Figlewicz, DA
通讯作者：
Figlewicz, DA
影响因子：
4.4
作者：
Bendotti, C;Calvaresi, N;De Biasi, S
通讯作者：
De Biasi, S
DOI：
10.1111/j.1749-6632.1996.tb18612.x
发表时间：
1996-01-01
期刊：
PEROXISOMES: BIOLOGY AND ROLE IN TOXICOLOGY AND DISEASE
影响因子：
--
作者：
Hiltunen, JK;Filppula, SA;Hayrinen, HM
通讯作者：
Hayrinen, HM
影响因子：
2.9
作者：
DALCANTO, MC;GURNEY, ME
通讯作者：
GURNEY, ME
影响因子：
4.2
作者：
ADAMO, AM;ALOISE, PA;PASQUINI, JM
通讯作者：
PASQUINI, JM