Genetic insights into OXPHOS defect and its role in cancer.
Genetic insights into OXPHOS defect and its role in cancer.
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DOI：
10.1016/j.bbabio.2010.10.023
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Singh KK
中科院分区：
文献类型：
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作者：
Chandra D;Singh KK
Warburg提出，癌症起源于线粒体氧化磷酸化(MtOXPHOS)的不可逆损伤，线粒体氧化磷酸化导致大多数癌症的有氧糖酵解率增加。然而，尽管与Warburg效应相关的研究已经有几十年了，但人们对癌症mtOXPHOS损伤的潜在遗传原因(S)知之甚少。参与mtOXPHOS的蛋白质既由线粒体DNA(MtDNA)编码，也由核DNA编码。这篇综述描述了线粒体DNA突变和线粒体DNA拷贝数减少是导致癌细胞OXPHOS缺陷的原因。母系遗传的mtDNA导致癌症易感性，而核编码基因的突变导致mtOXPHOS系统的缺陷。线粒体损伤检查点(MitoCheckpoint)在细胞核内诱导表观基因组的变化，从而逆转对OXPHOS的损伤。然而，对OXPHOS的不可逆损伤可导致持续性线粒体功能障碍，导致核基因组的遗传不稳定。总之，我们认为“有丝分裂检查点”导致的表观基因组和基因组变化在Warburg所描述的对OXPHOS的可逆和不可逆损伤中发挥了关键作用。这些表观遗传和遗传变化是Warburg表型的基础，而Warburg表型有助于癌症的发展。
Warburg proposed that cancer originates from irreversible injury to mitochondrial oxidative phosphorylation (mtOXPHOS), which leads to an increase rate of aerobic glycolysis in most cancers. However, despite several decades of research related to Warburg effect, very little is known about the underlying genetic cause(s) of mtOXPHOS impairment in cancers. Proteins that participate in mtOXPHOS are encoded by both mitochondrial DNA (mtDNA) as well as nuclear DNA. This review describes mutations in mtDNA and reduced mtDNA copy number, which contribute to OXPHOS defects in cancer cells. Maternally inherited mtDNA renders susceptibility to cancer, and mutation in the nuclear encoded genes causes defects in mtOXPHOS system. Mitochondria damage checkpoint (mitocheckpoint) induces epigenomic changes in the nucleus, which can reverse injury to OXPHOS. However, irreversible injury to OXPHOS can lead to persistent mitochondrial dysfunction inducing genetic instability in the nuclear genome. Together, we propose that “mitocheckpoint” led epigenomic and genomic changes must play a key role in reversible and irreversible injury to OXPHOS described by Warburg. These epigenetic and genetic changes underlie the Warburg phenotype, which contributes to the development of cancer.