A heteroplasmic, not homoplasmic, mitochondrial DNA mutation promotes tumorigenesis via alteration in reactive oxygen species generation and apoptosis
- 24 January 2009
- journal article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 18 (9), 1578-1589
- https://doi.org/10.1093/hmg/ddp069
Abstract
Mitochondrial alteration has been long proposed to play a major role in tumorigenesis. Recently, mitochondrial DNA (mtDNA) mutations have been found in a variety of cancer cells. In this study, we examined the contribution of mtDNA mutation and mitochondrial dysfunction in tumorigenesis first using human cell lines carrying a frame-shift at NADH dehydrogenase (respiratory complex I) subunit 5 gene (ND5); the same homoplasmic mutation was also identified in a human colorectal cancer cell line earlier. With increasing mutant ND5 mtDNA content, respiratory function including oxygen consumption and ATP generation through oxidative phosphorylation declined progressively, while lactate production and dependence on glucose increased. Interestingly, the reactive oxygen species (ROS) levels and apoptosis exhibited antagonistic pleiotropy associated with mitochondrial defects. Furthermore, the anchorage-dependence phenotype and tumor-forming capacity of cells carrying wild-type and mutant mtDNA were tested by growth assay in soft agar and subcutaneous implantation of the cells in nude mice. Surprisingly, the cell line carrying the heteroplasmic ND5 mtDNA mutation showed significantly enhanced tumor growth, while cells with homoplasmic form of the same mutation inhibited tumor formation. Similar results were obtained from the analysis of a series of mouse cell lines carrying a nonsense mutation at ND5 gene. Our results indicate that the mtDNA mutations might play an important role in the early stage of cancer development, possibly through alteration of ROS generation and apoptosis.Keywords
This publication has 52 references indexed in Scilit:
- Somatic mutations of mitochondrial genome in early stage breast cancerInternational Journal of Cancer, 2007
- Biochemical phenotypes associated with the mitochondrial ATP6 gene mutations at nt8993Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2007
- Caspase-8 dependent trail-induced apoptosis in cancer cell lines is inhibited by vitamin C and catalaseApoptosis, 2006
- Glutathione peroxidase, glutathione-S-transferase, catalase, xanthine oxidase, Cu–Zn superoxide dismutase activities, total glutathione, nitric oxide, and malondialdehyde levels in erythrocytes of patients with small cell and non-small cell lung cancerCancer Letters, 2005
- Genetic and Functional Analysis of Mitochondrial DNA‐Encoded Complex I GenesAnnals of the New York Academy of Sciences, 2004
- Serum Copper/Zinc Superoxide Dismutase (Cu/Zn SOD) and Gastric Cancer Risk: a Case-Control StudyJapanese Journal of Cancer Research, 2002
- Mitochondria, from cell death to proliferationNature Genetics, 2002
- Relevance of mitochondrial DNA in cancerThe Lancet, 2000
- Early superoxide dismutase-sensitive event promotes neoplastic transformation in mouse epidermal JB6 cellsCarcinogenesis: Integrative Cancer Research, 1988
- On the Origin of Cancer CellsScience, 1956