Genetic insights into OXPHOS defect and its role in cancer

被引:104
作者
Chandra, Dhyan [2 ]
Singh, Keshav K. [1 ]
机构
[1] Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA
[2] Roswell Pk Canc Inst, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA
来源
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS | 2011年 / 1807卷 / 06期
基金
美国国家卫生研究院;
关键词
OXPHOS defect; Cancer; Warburg effect; Mitocheckpoint; Epigenetic; Epigenetics; Epigenomis; Mitochondria; Genetic instability; Chromosomal instability; mtDNA; MITOCHONDRIAL-DNA MUTATIONS; II HEXOKINASE PROMOTER; BREAST-CANCER; SUCCINATE-DEHYDROGENASE; CELL-DEATH; GLUCOSE CATABOLISM; RESPIRATORY-CHAIN; G10398A POLYMORPHISM; GENOME INSTABILITY; POLYMERASE-GAMMA;
D O I
10.1016/j.bbabio.2010.10.023
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. This article is part of a Special Issue entitled: Bioenergetics of Cancer. (C) 2010 Elsevier B.V. All rights reserved.
引用
收藏
页码:620 / 625
页数:6
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