Sod1 loss induces intrinsic superoxide accumulation leading to p53-mediated growth arrest and apoptosis.
Sod1 loss induces intrinsic superoxide accumulation leading to p53-mediated growth arrest and apoptosis.
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DOI：
10.3390/ijms140610998
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发表时间：
2013-05-24
影响因子：
5.6
通讯作者：
Shimizu T
中科院分区：
文献类型：
--
作者：
Watanabe K;Shibuya S;Koyama H;Ozawa Y;Toda T;Yokote K;Shimizu T
氧化还原失衡引起的氧化损伤引起细胞和组织中与年龄相关的变化。超氧化物歧化酶（SOD）酶在抗氧化系统中起着重要作用，它们也催化超氧化物自由基（O2•−）。由于细胞质SOD （SOD1）的缺失导致多种类型小鼠组织出现类似衰老的表型，因此SOD1对于维持组织稳态至关重要。为了阐明SOD1的细胞功能，我们研究了SOD1缺陷成纤维细胞的细胞表型。我们证明了Sod1缺乏损害了成纤维细胞的增殖并诱导了与细胞质和线粒体中O2•−积累相关的细胞凋亡。Sod1缺失也降低了线粒体膜电位，导致DNA损伤介导的p53激活。抗氧化处理通过抑制sod1缺陷成纤维细胞内O2•−积累和p53激活，有效改善了细胞表型。体内实验显示，用维生素C衍生物进行透皮治疗可显著逆转皮肤变薄，这种变薄通常与皮肤中p53活性上调有关。我们的研究结果表明，内在的O2•−积累促进了p53介导的成纤维细胞生长停滞和凋亡以及线粒体功能障碍。
Oxidative damages induced by a redox imbalance cause age-related changes in cells and tissues. Superoxide dismutase (SOD) enzymes play a major role in the antioxidant system and they also catalyze superoxide radicals (O2•−). Since the loss of cytoplasmic SOD (SOD1) resulted in aging-like phenotypes in several types of mouse tissue, SOD1 is essential for the maintenance of tissue homeostasis. To clarify the cellular function of SOD1, we investigated the cellular phenotypes of Sod1-deficient fibroblasts. We demonstrated that Sod1 deficiency impaired proliferation and induced apoptosis associated with O2•− accumulation in the cytoplasm and mitochondria in fibroblasts. Sod1 loss also decreased the mitochondrial membrane potential and led to DNA damage-mediated p53 activation. Antioxidant treatments effectively improved the cellular phenotypes through suppression of both intracellular O2•− accumulation and p53 activation in Sod1-deficient fibroblasts. In vivo experiments revealed that transdermal treatment with a vitamin C derivative significantly reversed the skin thinning commonly associated with the upregulated p53 action in the skin. Our findings revealed that intrinsic O2•− accumulation promoted p53-mediated growth arrest and apoptosis as well as mitochondrial disfunction in the fibroblasts.
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影响因子：
2.7
作者：
Gannon HS;Donehower LA;Lyle S;Jones SN
通讯作者：
Jones SN
影响因子：
50.3
作者：
Hamard PJ;Manfredi JJ
通讯作者：
Manfredi JJ
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影响因子：
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影响因子：
13.8
作者：
Ditch, Scott;Paull, Tanya T.
通讯作者：
Paull, Tanya T.
影响因子：
64.5
作者：
Kruse JP;Gu W
通讯作者：
Gu W