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Transcriptome analysis from Nd2-mutant and control fibroblasts

ABSTRACT: Background: Mutations of mitochondrial (mt)DNA cause a variety of human diseases and are also implicated in ageing processes. Results: Primary fibroblasts of the conplastic mouse strain C57BL/6J-mtALR/LTJ with a mutation at position nt4738 resulting in a single nucleotide exchange (leucine to methionine) in the mitochondrial NADH dehydrogenase subunit 2 (Nd2) gene of the respiratory chain show higher enzyme activity and ATP production and lower ROS production than control fibroblasts. Furthermore, Nd2-mutant fibroblasts show a higher proliferation rate and a reduction of senescence markers. Transcriptome analysis reveals members of the p38MAPK pathway as being significantly downregulated in Nd2-mutant mice as compared with controls. In line with this, inhibition of p38MAPK with SB203580 enhanced the proliferation and reduced cytokine secretion in senescent Nd2-mutant fibroblasts. Conclusion: Taken together, we report Nd2 as a new mitochondrial gene with age-protective function in mice, and possibly in humans, which interferes with age-related signaling pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE63551 | GEO | 2014/11/22

SECONDARY ACCESSION(S): PRJNA268188

REPOSITORIES: GEO

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Project description:This is the model described in: Feedback between p21 and reactive oxygen production is necessary for cell senescence. Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TB, von Zglinicki T. ;Mol Sys Biol2010;6:347. Epub 2010 Feb 16. PMID:20160708 doi:10.1038/msb.2010.5; Abstract: Cellular senescence--the permanent arrest of cycling in normally proliferating cells such as fibroblasts--contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of 'deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 The BioModels.net Team.For more information see the terms of use.To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Transcriptome analysis from Nd2-mutant and control fibroblasts

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