title: A mutation in the NADH-dehydrogenase subunit 2 suppresses fibroblast aging.
abstract: Mutations of mitochondrial (mt)DNA cause a variety of human diseases and are implicated in premature aging syndromes. Here we investigated a single nucleotide exchange (leucine to methionine) at position nt4738 in the mitochondrial NADH dehydrogenase subunit 2 (Nd2) gene of the respiratory chain. Primary fibroblasts derived from the conplastic mouse strain C57BL/6J-mtALR/LTJ with mutant enzyme, possessed high enzyme activity and ATP production and low ROS production. Furthermore, Nd2-mutant fibroblasts expressed lower senescence markers. Transcriptome analysis revealed that the members of the p38MAPK pathway were significantly downregulated in Nd2-mutant mice. In agreement, inhibition of p38MAPK with SB203580 enhanced proliferation and reduced cytokine secretion in fibroblasts. In Nd2-mutant mouse skin, the amount of Ki67-positive cells was significantly higher than in control skin. The higher amount of Ki67-positive cells and the thicker epidermis in Nd2-mutant mice strongly supported the in vitro data. In conclusion, Nd2 is a mitochondrial gene, involved in age-related signaling pathways.
authors.affiliation: Department of Dermatology, Venereology and Allergology, University of Leipzig, Leipzig 04103, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Schauer
authors.affiliation: Department of Dermatology, Venereology and Allergology, University of Leipzig, Leipzig 04103, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Kottek
authors.affiliation: Department of Dermatology, Venereology and Allergology, University of Leipzig, Leipzig 04103, Germany.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Schönherr
authors.affiliation: Department of Dermatology, Venereology and Allergology, University of Leipzig, Leipzig 04103, Germany.
authors.forename: Animesh
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck 23538, Germany.
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
authors.affiliation: Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck 23538, Germany.
authors.forename: Misa
authors.initials: M
authors.lastname: Hirose
authors.affiliation: Department of Physiology, University of Rostock, Rostock 18057, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Köhling
authors.affiliation: Department of Biostatistics and Informatics in Medicine and Ageing Research, University of Rostock, Rostock 18057, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Fuellen
authors.affiliation: Department of Systems Biology and Bioinformatics, University of Rostock, Rostock 18057, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schmitz
authors.affiliation: Department of Dermatology, Venereology and Allergology, University of Leipzig, Leipzig 04103, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kunz
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D004579:Electron Transport / Q000235:genetics; D004817:Epidermis / Q000648:ultrastructure*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000032:analysis; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology; D020125:Mutation, Missense; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000502:physiology; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000235:genetics; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D004272:DNA, Mitochondrial; D007093:Imidazoles; D019394:Ki-67 Antigen; C000604649:NADH dehydrogenase subunit 2, mouse; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D004317:Doxorubicin; D009245:NADH Dehydrogenase; C093642:SB 203580
keywords: aging; mitochondria; p38MAPK signalling; senescence; skin fibroblasts
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