Chandra Dhyan, Singh Keshav K
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Biochim Biophys Acta. 2011 Jun;1807(6):620-5. doi: 10.1016/j.bbabio.2010.10.023. Epub 2010 Nov 11.
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.
瓦尔堡提出，癌症起源于线粒体氧化磷酸化（mtOXPHOS）的不可逆损伤，这导致大多数癌症中糖酵解速率增加。然而，尽管对瓦尔堡效应进行了数十年的研究，但对于癌症中mtOXPHOS损伤的潜在遗传原因却知之甚少。参与mtOXPHOS的蛋白质由线粒体DNA（mtDNA）和核DNA共同编码。本综述描述了mtDNA中的突变和mtDNA拷贝数的减少，这些因素导致癌细胞中的氧化磷酸化缺陷。母系遗传的mtDNA使个体易患癌症，而核编码基因中的突变会导致mtOXPHOS系统出现缺陷。线粒体损伤检查点（mitocheckpoint）会诱导细胞核中的表观基因组变化，从而可以逆转对氧化磷酸化的损伤。然而，对氧化磷酸化的不可逆损伤会导致持续的线粒体功能障碍，进而诱导核基因组中的遗传不稳定。我们共同提出，“mitocheckpoint”导致的表观基因组和基因组变化必定在瓦尔堡所描述的氧化磷酸化的可逆和不可逆损伤中起关键作用。这些表观遗传和遗传变化是瓦尔堡表型的基础，而瓦尔堡表型有助于癌症的发展。
