Genetic insights into OXPHOS defect and its role in cancer

• Published in: Biochimica et biophysica acta 2011-06, Vol.1807 (6), p.620-625
• Main Authors: Chandra, Dhyan, Singh, Keshav K.
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Chromosomal instability; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Epigenetic; Epigenetics; Epigenomis; genes; Genes, Mitochondrial - physiology; Genetic instability; glycolysis; Humans; Mitocheckpoint; Mitochondria; Mitochondrial Diseases - complications; Mitochondrial Diseases - genetics; mitochondrial DNA; Models, Biological; mtDNA; mutation; neoplasm cells; neoplasms; Neoplasms - etiology; Neoplasms - genetics; Neoplasms - metabolism; nuclear genome; Oxidative Phosphorylation; OXPHOS defect; phenotype; proteins; Warburg effect
• ISSN: 0005-2728; 0006-3002; 1879-2650
• DOI: 10.1016/j.bbabio.2010.10.023

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. ►Injury to OXPHOS induces mitocheckpoint response. ►Mitocheckpoint regulates reversible epigenomic changes in the nucleus. ►Irreversible injury to OXPHOS induces genetic instability in the nuclear genome. ►Defective OXPHOS-induced epigenetic/genetic changes may lead to development of cancer.