Alterations of Mitochondrial DNA in Common Diseases and Disease States: Aging, Neurodegeneration, Heart Failure, Diabetes and Cancer

• Published in: Current medicinal chemistry Vol. 12; no. 4; pp. 429 - 441
• Main Authors: Kang, Dongchon, Hamasaki, Naotaka
• Format: Journal Article
• Language: English
• Published: Schiphol Bentham Science Publishers Ltd 01.02.2005; Bentham Science
• Subjects: Age Factors; Aging; Animals; Binding sites; Biological and medical sciences; Cancer; Carcinogenesis, carcinogens and anticarcinogens; Cardiac Output, Low - etiology; Cardiac Output, Low - genetics; Cardiomyocytes; Cations; Cell differentiation; Cell metabolism, cell oxidation; Cell physiology; Cell structures and functions; Chemical damage; Congestive heart failure; Cytochrome; Deoxyribonucleic acid; Diabetes; Diabetes mellitus; Diabetes Mellitus - etiology; Diabetes Mellitus - genetics; Disease Models, Animal; DNA; DNA damage; DNA repair; DNA, Mitochondrial - chemistry; DNA, Mitochondrial - genetics; Fundamental and applied biological sciences. Psychology; General aspects; Genetic disorders; Genomes; Heart diseases; Heart failure; HIV; Human immunodeficiency virus; Humans; Lipid peroxidation; Lipids; Lipophilic; Lipophilicity; Medical sciences; Membrane potential; Membranes; Metabolism; Mice; Mitochondria; Mitochondria and cell respiration; Mitochondrial Diseases - etiology; Mitochondrial Diseases - genetics; Mitochondrial DNA; Molecular and cellular biology; Mutagenesis; Mutation; Myopathy; Neoplasms - etiology; Neoplasms - genetics; Neurodegeneration; Neurodegenerative Diseases - etiology; Neurodegenerative Diseases - genetics; Oxidative phosphorylation; Oxidative stress; Parkinson Disease - etiology; Parkinson Disease - genetics; Pathogenesis; Phosphorylation; Physiology; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reagents; Respiration; Side effects; Signal transduction; Somatic cells; Tumors; Zidovudine; Endocrinopathy; Oxidative stress; Pathogenesis; Toxicity; DNA damage; Alteration; Parkinson disease; Cardiovascular disease; Mitochondrial DNA; reactive oxygen species (ROS); Carcinogenesis; DNA repair; Mitochondria; Heart disease; Antiviral; Degenerative disease; Repair; Heart failure; Nervous system diseases; Diabetes mellitus; Ageing; Malignant tumor; Cerebral disorder; Central nervous system disease; Lesion; aging; Zidovudine
• ISSN: 0929-8673; 1875-533X
• DOI: 10.2174/0929867053363081

It has long been considered that mitochondrial DNA disease is a rare genetic disorder causing neuromyopathy. However, alterations of mitochondrial DNA recently have been recognized to play an important role in the pathogenesis of so-called common diseases such as heart failure, diabetes, and cancer. Although some of these alterations are inherited, more and more attention is being focused on the accumulation of mitochondrial DNA mutations in somatic cells, particularly terminally differentiated cells such as cardiomyocytes and neurons that occurs with age. Mitochondrial DNA is more vulnerable to alteration than nuclear DNA, mainly for two reasons. First, mitochondria are a major source of intracellular reactive oxygen species (ROS). Therefore mitochondrial DNA is under much stronger oxidative stress than is nuclear DNA. Second, mitochondria have a matrix-side negative membrane potential for oxidative phosphorylation. This membrane potential concentrates lipophilic cations inside mitochondria up to ~1,000-fold. Unfortunately, some therapeutic reagents are lipophilic cations, and such exogenously added chemicals are prone to damage mitochondria. AZT, an anti-HIV drug, causes mitochondrial myopathy as a side effect, which is a typical example of how chemotherapeutics adversely affect metabolism of mitochondrial DNA. In this review, we focus on ROS and chemical damage of mitochondrial DNA in common diseases.