Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation.
Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation.
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DOI：
10.1371/journal.pone.0002009
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发表时间：
2008-04-23
期刊：
影响因子：
3.7
通讯作者：
Qi H
中科院分区：
文献类型：
--
作者：
Fu X;Wan S;Lyu YL;Liu LF;Qi H
DNA损伤，如双链DNA断裂（DSB）已被报道刺激线粒体生物合成。然而，对潜在的机制知之甚少。对DSB反应的主要参与者是ATM（共济失调毛细血管扩张突变）。在感测DSB时，ATM通过自磷酸化被激活，并磷酸化用于DNA修复、细胞周期调节和凋亡的许多底物。ATM可磷酸化AMP活化蛋白激酶（AMPK）的α亚基，并可被上游激酶激活。在这里，我们提供了一个新的作用，ATM的线粒体生物合成的证据，通过AMPK激活依托泊苷诱导的DNA损伤。采用三对人类ATM+和ATM-细胞。通过10-N-壬基-吖啶橙子和MitoTracker绿色FM染色测量，用依托泊苷处理的细胞表现出线粒体质量的ATM依赖性增加，以及线粒体DNA含量的增加。此外，通过RT-PCR监测，几种已知的线粒体生物合成调节因子如主要线粒体转录因子NRF-1、PGC-1α和TFAM的表达也响应于依托泊苷处理而升高。三个证据表明，依托泊苷诱导的线粒体生物合成是由于ATM依赖性激活AMPK。首先，依托泊苷诱导AMPK α亚基在Thr 172的ATM依赖性磷酸化，表明AMPK活化。第二，AMPK的抑制阻断了依托泊苷诱导的线粒体生物合成。第三，通过AICAR（AMP类似物）激活AMPK以ATM依赖的方式刺激线粒体生物合成，表明ATM可能是AMPK在线粒体生物合成途径中的上游激酶。这些结果表明，依托泊苷激活ATM可以通过AMPK激活导致线粒体生物合成。我们认为ATM依赖的线粒体生物合成可能在DNA损伤反应和ROS调节中发挥作用，ATM依赖的线粒体生物合成缺陷可能导致A-T疾病的表现。
DNA damage such as double-stranded DNA breaks (DSBs) has been reported to stimulate mitochondrial biogenesis. However, the underlying mechanism is poorly understood. The major player in response to DSBs is ATM (ataxia telangiectasia mutated). Upon sensing DSBs, ATM is activated through autophosphorylation and phosphorylates a number of substrates for DNA repair, cell cycle regulation and apoptosis. ATM has been reported to phosphorylate the α subunit of AMP-activated protein kinase (AMPK), which senses AMP/ATP ratio in cells, and can be activated by upstream kinases. Here we provide evidence for a novel role of ATM in mitochondrial biogenesis through AMPK activation in response to etoposide-induced DNA damage. Three pairs of human ATM+ and ATM- cells were employed. Cells treated with etoposide exhibited an ATM-dependent increase in mitochondrial mass as measured by 10-N-Nonyl-Acridine Orange and MitoTracker Green FM staining, as well as an increase in mitochondrial DNA content. In addition, the expression of several known mitochondrial biogenesis regulators such as the major mitochondrial transcription factor NRF-1, PGC-1α and TFAM was also elevated in response to etoposide treatment as monitored by RT-PCR. Three pieces of evidence suggest that etoposide-induced mitochondrial biogenesis is due to ATM-dependent activation of AMPK. First, etoposide induced ATM-dependent phosphorylation of AMPK α subunit at Thr172, indicative of AMPK activation. Second, inhibition of AMPK blocked etoposide-induced mitochondrial biogenesis. Third, activation of AMPK by AICAR (an AMP analogue) stimulated mitochondrial biogenesis in an ATM-dependent manner, suggesting that ATM may be an upstream kinase of AMPK in the mitochondrial biogenesis pathway. These results suggest that activation of ATM by etoposide can lead to mitochondrial biogenesis through AMPK activation. We propose that ATM-dependent mitochondrial biogenesis may play a role in DNA damage response and ROS regulation, and that defect in ATM-dependent mitochondrial biogenesis could contribute to the manifestations of A-T disease.
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影响因子：
5.1
作者：
AMMANN, AJ;HONG, R
通讯作者：
HONG, R
DOI：
10.1001/archpedi.1967.02090270073006
发表时间：
1967-01-01
影响因子：
--
作者：
GOTOFF, SP;AMIRMOKRI, E;LIEBNER, EJ
通讯作者：
LIEBNER, EJ
影响因子：
7.4
作者：
Browne, SE;Roberts, LJ;Levine, RL
通讯作者：
Levine, RL
影响因子：
64.5
作者：
Barlow, C;Hirotsune, S;WynshawBoris, A
通讯作者：
WynshawBoris, A
DOI：
10.1073/pnas.93.23.13084
发表时间：
1996-11-12
影响因子：
11.1
作者：
Elson, A;Wang, YQ;Leder, P
通讯作者：
Leder, P