how do human cells react to the absence of mitochondrial dna人类细胞如何应对缺乏线粒体dna的.pdfVIP

How Do Human Cells React to the Absence of Mitochondrial DNA? 1. 2.¤ 1 3 Rossana Mineri , Norman Pavelka , Erika Fernandez-Vizarra , Paola Ricciardi-Castagnoli , Massimo 1 1 Zeviani , Valeria Tiranti * 1 Unit of Molecular Neurogenetics – Pierfranco and Luisa Mariani Center for the study of Mitochondrial Disorders in Children, IRCCS Foundation Neurological Institute ‘‘C. Besta’’, Milan, Italy, 2 Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milano, Italy, 3 Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore Abstract Background: Mitochondrial biogenesis is under the control of two different genetic systems: the nuclear genome (nDNA) and the mitochondrial genome (mtDNA). The mtDNA is a circular genome of 16.6 kb encoding 13 of the approximately 90 subunits that form the respiratory chain, the remaining ones being encoded by the nDNA. Eukaryotic cells are able to monitor and respond to changes in mitochondrial function through alterations in nuclear gene expression, a phenomenon first defined in yeast and known as retrograde regulation. To investigate how the cellular transcriptome is modified in response to the absence of mtDNA, we used Affymetrix HG-U133A GeneChip arrays to study the gene expression profile of two human cell lines, 143BTK2 and A549, which had been entirely depleted of mtDNA (ru cells), and compared it with that of corresponding undepleted parental cells (r+ cells). Results: Our data indicate that absence of mtDNA is associated with: i) a down-regulation of cell cycle control genes and a reduction of cell replication rate, ii) a down-regul