Mitochondrial dysfunction in ataxia-telangiectasia
Mitochondrial dysfunction in ataxia-telangiectasia
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DOI：
10.1182/blood-2011-08-373639
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发表时间：
2012-02-09
期刊：
影响因子：
20.3
通讯作者：
Kastan, Michael B.
中科院分区：
文献类型：
--
作者：
Valentin-Vega, Yasmine A.;MacLean, Kirsteen H.;Kastan, Michael B.
ataxia -毛细血管扩张突变（ATM）在DNA损伤反应中起核心作用，其缺失导致t细胞恶性肿瘤的发展。在这里，我们发现ATM丢失也导致胸腺细胞内在的线粒体异常，包括活性氧升高，异常线粒体增加，细胞呼吸能力高，线粒体自噬减少。ATM蛋白的一部分定位于线粒体，并在线粒体功能障碍时被迅速激活。出乎意料的是，自噬调节因子Beclin-1的等位基因缺失显著延缓了atm缺失小鼠的肿瘤发展。这种效果与DNA损伤信号的修复无关，而是与线粒体异常的显著逆转有关。这些数据支持ATM在调节线粒体稳态中起直接作用的模型，并表明线粒体功能障碍和线粒体活性氧的相关增加有助于在缺乏ATM的生物体中观察到的易患癌症的表型。因此，共济失调-毛细血管扩张应该被认为是一种线粒体疾病，至少部分是这样。[血液学报，2012;119(6):1490-1500]
Ataxia-telangiectasia mutated (ATM) plays a central role in DNA damage responses, and its loss leads to development of T-cell malignancies. Here, we show that ATM loss also leads to intrinsic mitochondrial abnormalities in thymocytes, including elevated reactive oxygen species, increased aberrant mitochondria, high cellular respiratory capacity, and decreased mitophagy. A fraction of ATM protein is localized in mitochondria, and it is rapidly activated by mitochondrial dysfunction. Unexpectedly, allelic loss of the autophagy regulator Beclin-1 significantly delayed tumor development in ATM-null mice. This effect was not associated with rescue of DNA damage signaling but rather with a significant reversal of the mitochondrial abnormalities. These data support a model in which ATM plays direct roles in modulating mitochondrial homeostasis and suggest that mitochondrial dysfunction and associated increases in mitochondrial reactive oxygen species contribute to the cancer-prone phenotype observed in organisms lacking ATM. Thus, ataxia-telangiectasia should be considered, at least in part, as a mitochondrial disease. (Blood. 2012; 119(6): 1490-1500)