developmental and pathological changes in the human cardiac muscle mitochondrial dna organization, replication and copy number发育和病理变化在人类心肌线粒体dna组织、复制和拷贝数.pdfVIP

Developmental and Pathological Changes in the Human Cardiac Muscle Mitochondrial DNA Organization, Replication and Copy Number ¨ 1 2 3 3 4 Jaakko L. O. Pohjoismaki *, Steffi Goffart , Robert W. Taylor , Douglas M. Turnbull , Anu Suomalainen , Howard T. Jacobs2, Pekka J. Karhunen1 1 Department of Forensic Medicine, Medical School, University of Tampere, Tampere, Finland, 2 Institute of Medical Technology, University of Tampere, Tampere, Finland, 3 Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom, 4 Research Program of Molecular Neurology, University of Helsinki, Helsinki, Finland Abstract Adult human heart mitochondrial DNA (mtDNA) has recently been shown to have a complex organization with abundant dimeric molecules, branched structures and four-way junctions. In order to understand the physiological significance of the heart-specific mtDNA maintenance mode and to find conditions that modify human heart mtDNA structure and replication, we analyzed healthy human heart of various ages as well as several different heart diseases, including ischemic heart disease, dilated as well as hypertrophic cardiomyopathies, and several mitochondrial disorders. By using one- and two- dimensional agarose gel electrophoresis, various enzymatic treatments and quantitative PCR we found that in human newborns heart mtDNA has a simple organization, lacking junctional forms and dimers. The adult-type branched forms are acquired in the early childhood, correlating with an increase in mtDNA copy number. Mitochondrial disorders involving either mutations in the mtDNA polymerase c (PolGa) or mtDNA