title: Global variability in gene expression and alternative splicing is modulated by mitochondrial content.
abstract: Noise in gene expression is a main determinant of phenotypic variability. Increasing experimental evidence suggests that genome-wide cellular constraints largely contribute to the heterogeneity observed in gene products. It is still unclear, however, which global factors affect gene expression noise and to what extent. Since eukaryotic gene expression is an energy demanding process, differences in the energy budget of each cell could determine gene expression differences. Here, we quantify the contribution of mitochondrial variability (a natural source of ATP variation) to global variability in gene expression. We find that changes in mitochondrial content can account for ∼50% of the variability observed in protein levels. This is the combined result of the effect of mitochondria dosage on transcription and translation apparatus content and activities. Moreover, we find that mitochondrial levels have a large impact on alternative splicing, thus modulating both the abundance and type of mRNAs. A simple mathematical model in which mitochondrial content simultaneously affects transcription rate and splicing site choice can explain the alternative splicing data. The results of this study show that mitochondrial content (and/or probably function) influences mRNA abundance, translation, and alternative splicing, which ultimately affects cellular phenotype.
authors: Department of Condensed Matter Physics, Materials Science Institute "Nicolás Cabrera" and Institute of Condensed Matter Physics (IFIMAC), Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid, Spain;
authors: Raul
authors: R
authors: Guantes
authors: Centro Biología Molecular "Severo Ochoa," CSIC-UAM, Campus de Cantoblanco, 28049 Madrid, Spain;
authors: Alberto
authors: A
authors: Rastrojo
authors: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom;
authors: Ricardo
authors: R
authors: Neves
authors: UC Biotech, Center for Neuroscience and Cell Biology, Biocant, Center of Innovation in Biotechnology, 3060-197 Cantanhede, Portugal;
authors: Ana
authors: A
authors: Lima
authors: Centro Biología Molecular "Severo Ochoa," CSIC-UAM, Campus de Cantoblanco, 28049 Madrid, Spain;
authors: Begoña
authors: B
authors: Aguado
authors: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom; Centro Nacional de Biotecnología, CSIC, Campus de Cantoblanco, 28049 Madrid, Spain.
authors: Francisco J
authors: FJ
authors: Iborra
mesh_terms: D017398:Alternative Splicing; D004272:DNA, Mitochondrial / Q000235:genetics*; D004734:Energy Metabolism; D014644:Genetic Variation; D016678:Genome; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D012333:RNA, Messenger