Mitochondrial peptidase IMMP2L mutation causes early onset of age-associated disorders and impairs adult stem cell self-renewal.
Mitochondrial peptidase IMMP2L mutation causes early onset of age-associated disorders and impairs adult stem cell self-renewal.
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DOI：
10.1111/j.1474-9726.2011.00686.x
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发表时间：
2011-08
期刊：
影响因子：
7.8
通讯作者：
Lu B
中科院分区：
文献类型：
--
作者：
George SK;Jiao Y;Bishop CE;Lu B
尽管缺乏直接的体内证据，但线粒体活性氧（ROS）被认为在衰老和年龄相关疾病中发挥着核心作用。我们最近培育了一种内线粒体膜肽酶 2 样 (Immp2l) 基因突变的小鼠突变体，该基因会损害线粒体蛋白细胞色素 c1 和磷酸甘油脱氢酶 2 的信号肽序列处理。突变小鼠的线粒体产生超氧离子水平升高，导致两性生育能力受损。在这里，我们设计实验来检查线粒体 ROS 生成过多对健康寿命的影响。我们发现 Immp2l 突变会增加大脑和肾脏等多个器官的氧化应激，尽管突变体这些组织中超氧化物歧化酶的表达也有所增加。这些突变体表现出多种与衰老相关的表型，包括消瘦、肌肉减少症、皮下脂肪减少、驼背和共济失调，其中女性突变体比男性突变体表现出更早的发病和更严重的年龄相关疾病。体重和脂肪的减少与食物摄入量无关。来自突变小鼠的脂肪源性基质细胞（ADSC）显示出增殖能力受损，在集落形成测定中形成的集落明显更少且更小，尽管它们在体外保留了成脂分化能力。这种功能障碍伴随着氧化应激水平的增加。我们的数据表明，线粒体活性氧是加速衰老的驱动力，并表明活性氧对成体干细胞的损伤可能是与年龄相关的疾病的机制之一。
Mitochondrial reactive oxygen species (ROS) are proposed to play a central role in aging and age-associated disorders, although direct in vivo evidence is lacking. We recently generated a mouse mutant with mutated Inner Mitochondrial Membrane Peptidase 2-like (Immp2l) gene, which impairs the signal peptide sequence processing of mitochondrial proteins cytochrome c1 and glycerol phosphate dehydrogenase 2. The mitochondria from mutant mice generate elevated levels of superoxide ion and cause impaired fertility in both sexes. Here we design experiments to examine the effects of excessive mitochondrial ROS generation on health span. We show that Immp2l mutation increases oxidative stress in multiple organs such as the brain and the kidney, although expression of superoxide dismutases in these tissues of the mutants is also increased. The mutants show multiple aging-associated phenotypes, including wasting, sarcopenia, loss of subcutaneous fat, kyphosis and ataxia, with female mutants showing earlier onset and more severe age-associated disorders than male mutants. The loss of body weight and fat was unrelated to food intake. Adipose derived stromal cells (ADSC) from mutant mice showed impaired proliferation capability, formed significantly less and smaller colonies in colony formation assays, although they retained adipogenic differentiation capability in vitro. This functional impairment was accompanied by increased levels of oxidative stress. Our data showed that mitochondrial ROS is the driving force of accelerated aging and suggested that ROS damage to adult stem cells could be one of the mechanisms for age-associated disorders.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
DOI：
10.1111/j.1532-5415.1972.tb00787.x
发表时间：
1972-01-01
影响因子：
6.3
作者：
HARMAN, D
通讯作者：
HARMAN, D
影响因子：
4.1
作者：
Bayne, ACV;Mockett, RJ;Sohal, RS
通讯作者：
Sohal, RS
影响因子：
2.9
作者：
CHUMLEA W C;RHYNE R L;HUNT W C
通讯作者：
HUNT W C
影响因子：
1.5
作者：
Haines, DC;Chattopadhyay, S;Ward, JM
通讯作者：
Ward, JM