[Frontiers in Bioscience 15, 437-460, January 1, 2010]

Mitochondrial DNA mutations in cancer - from bench to bedside

Anna Malgorzata Czarnecka1,2, Wojciech Kukwa3, Tomasz Krawczyk4, Anna Scinska3, Andrzej Kukwa3, Francesco Cappello5

1Postgraduate School of Molecular Medicine, Medical University of Warsaw, ul. Zwirki I Wigury 61, 02-091 Warsaw, Poland, 2Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, ul. Pawinskiego 5a, 02 - 106 Warsaw, Poland, 3 Department of Otolaryngology, Czerniakowski Hospital, Medical University of Warsaw, ul. Stepinska 19/25, 00-739 Warsaw, Poland,4Clinical Pathology Laboratory, Monument Institute of Polish Mothers Health Center, ul. Rzgowska 281/289, 93-316 Lodz, Poland, 5Human Anatomy Section, Department of Experimental Medicine, University of Palermo, via del Vespro 129, 90127 Palermo, Italy


1. Abstract
2. Introduction
2.1. MtDNA mutation mechanism
2.2. The role of reactive oxygen species in mitochondrial carcinogenesis
3. D-loop mutations in human cancers
3.1. Consequences for cell physiology
3.2. Clinical implications
4. tRNA genes mutations in human cancers
4.1. Consequences for cell physiology
4.2. Clinical implications
5. rRNA genes mutations
6. OXPHOS complex I genes and human cancer
6.1. Consequences for cell physiology
6.2. Clinical implications
7. OXPHOS complex III genes
7.1. Consequences for cell physiology
8. OXPHOS complex IV genes and human cancer
8.1. Consequences for cell physiology
8.2. Clinical implications
9. OXPHOS complex V genes and human cancers
9.1. Consequences for cell physiology
9.2. Clinical implications
10. Large mtDNA deletions and mtDNA depletion in human cancers
11. OXPHOS genes expression in human cancers
12. Summary and perspectives
13. Acknowledgements
14. References


Mitochondria are cell organelles mostly known for their production of ATP through oxidative phosphorylation. As suggested over 70 years ago by O. Warburg and recently confirmed with molecular techniques, alterations in respiratory activity and mitochondrial DNA appear to be a common feature of malignant cells. Somatic mtDNA mutations have been reported in many types of cancer cells. MtDNA mutation pattern may enhance the specificity of cancer diagnostics, detection and prediction of tumor growth rate and patients' outcome. Therefore it may be used as a molecular cancer bio-marker. Nevertheless recently published papers list a large number of mitochondrial DNA mutations in many different cancer types, but their role in cell patophysiology remains unsummarized. This review covers the consequences of mitochondrial genes mutations for human cell physiology and proliferation. We underline effects of mtDNA mutation-resulting amino acid changes in the respiratory chain proteins' structure, and propose changes in mitochondrial protein function. Mutations are critically evaluated and interpreted in the functional context and clinical utility of molecular mitochondrial research is summarized and new perspectives for 'mitochondrial oncology' suggested.