TY - JOUR
T1 - A mutation in the NADH-dehydrogenase subunit 2 suppresses fibroblast aging
AU - Schauer, Marianne
AU - Kottek, Tina
AU - Schönherr, Madeleine
AU - Bhattacharya, Animesh
AU - Ibrahim, Saleh M.
AU - Hirose, Misa
AU - Köhling, Rüdiger
AU - Fuellen, Georg
AU - Schmitz, Ulf
AU - Kunz, Manfred
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84928749710&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.3298
DO - 10.18632/oncotarget.3298
M3 - Journal articles
C2 - 25839158
AN - SCOPUS:84928749710
SN - 1949-2553
VL - 6
SP - 8552
EP - 8566
JO - Oncotarget
JF - Oncotarget
IS - 11
ER -