Interested in Mitochondrial DNA and mitochondrial function?

1. wt, men csb-/-, men mtDNA menadione nontreated wt csb-/- wt csb-/- - Intact strand Increased fragmentation + Denaturing Southern Analysis 20 nM TMRM 20 nM TMRM Impact of Mitochondrial Damage and Dysfunction in Hematochromatosis Lars Eide* and Lars Mørkrid Iron metabolism is a complicated process. Dietary iron needs to be taken up, transported, delivered and assembled into proteins, where it serves essential redox and structural roles. Defects in different aspects of iron metabolism result in several human diseases, such as iron deficiency anemia, hemochomatosis, haemosiderosis, and may be involved in the pathophysiological mechanism of disorders like Friedrich Ataxia, type II Diabetes and heart failure. Although essential, divalent iron can also be toxic due to its ability to generate free radicals. More than 90% of oxygen taken up by the cell is reduced by the mitochondria in the “healthy” mode, but a minor but significant part of this oxygen (2-5%) results in generation of reactive oxygen species, such as hydrogen peroxide. The toxic role of iron is attributed to its ability to convert hydrogen peroxide into the more reactive and dangerous hydroxyl radical. Iron is on the other hand abundant in the mitochondria as it is an essential cofactor in several mitochondrial electron transport proteins. Thus, fine-tuned balance of the iron level is essential to both preserve mitochondrial function and to diminish detrimental effect of toxic side reactions. Hematochromatosis is often associated with liver fibrosis, chirrhosis, and the development of neoplasias (malignant hepatomas). Necrosis and apoptosis are conducted by the mitochondria hence it is plausible that mitochondria as well might play an important role in cell and tissue degeneration associated with hematochromatosis. In this project, the impact of mitochondrial damage will be examined during conditions of elevated iron, such as in hematochromatosis. Initial experiments will include evaluation of mitochondrial function and mitochondrial DNA in fibroblast cell lines exposed to various iron levels. These studies will serve as template to investigate iron sensitivity in hepatocytes. We have available genetically modified mice with defective mtDNA repair function. These will provide tools for examining the role of proper mtDNA maintenance in protection against chronic iron overload-induced damage. The department of medical biochemistry has an out-patient clinic for patients with hemochromatosis, from which it will be possible to recruit material for investigations on human material. At The institute of Clinical Biochemistry, we have available technology to investigate mitochondrial function in vivo and in vitro, as well as tools to measure DNA integrity. The candidate will be a part of an active research environment consisting of more than 15 Technicians, Master Students, PhD students and PostDocs at the institute of Clinical Biochemistry, University of Oslo, Rikshospitalet-Radiumhospitalet Medical Hospital. Interested in Mitochondrial DNA and mitochondrial function? Join the Mitogroup at Institute of Clinical Biochemistry, University of Oslo, Rikshospitalet, and Centre for Molecular Biology and Neuroscience INTRODUCTION Facilities Mitochondrial function is essential for life. Increasing attention is paid to mitochondrial dysfunction as this is coupled to many metabolic and age-related diseases such as Cancer, Parkinson’s and Alzheimers Disease. At the institute of Clinical Biochemistry, we are focusing on the impact of mitochondrial DNA (mtDNA) on the mitochondrial function. Accumulation of damages to this DNA increases with ageing, and result in reduced bioenergetic capacity. Different genetic and environmental factors contribute to the speed at which the mtDNA is erroded. These include oxidative stress, reduced mtDNA maintenance and life-style-related metabolism. In collaboration with the Dept. Medical Biochemistry, we are investigating the impact of mitochondrial dysfunction in metabolic diseases. We are located at Rikshospitalet, 3rd floor in the B building. The laboratory houses approximately 20 persons, including Students, Technicians, PhD students and PostDocs; The research group is an associated member of the Centre of Molecular Biology and Neuroscience; on of the Centre’s of Excellence in Oslo. The Mitogroup members Projects Analysis of mitochondrial involvement in Cockayne’s Syndrome Regulation of mtDNA repair and consequences for apoptosis Bioenergetic regulation by mtDNA integrity Mitochondrial dysfunction in Huntington’s Disease Proposed project: Mitochondrial dysfunction in Hematochromatosis * Contact information; Lars Eide, Institute of Clinical Biochemistry, Rikshospitalet, UiO, B1.3002 phone: 23070947, 93241242, lars.eide@medisin.uio.no