A mutation in the NADH-dehydrogenase subunit 2 suppresses fibroblast aging

Oncotarget. 2015 Apr 20;6(11):8552-66. doi: 10.18632/oncotarget.3298.


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.

Keywords: aging; mitochondria; p38MAPK signalling; senescence; skin fibroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Cell Division
  • Cells, Cultured
  • Cellular Senescence / genetics*
  • DNA, Mitochondrial / genetics
  • Down-Regulation
  • Doxorubicin / pharmacology
  • Electron Transport / genetics
  • Epidermis / ultrastructure*
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / enzymology*
  • Fibroblasts / metabolism
  • Imidazoles / pharmacology
  • Ki-67 Antigen / analysis
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / physiology
  • Mutation, Missense*
  • NADH Dehydrogenase / genetics*
  • NADH Dehydrogenase / physiology
  • Oxidative Phosphorylation
  • Oxidative Stress / genetics
  • Point Mutation*
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines / pharmacology
  • Transcriptome


  • DNA, Mitochondrial
  • Imidazoles
  • Ki-67 Antigen
  • NADH dehydrogenase subunit 2, mouse
  • Protein Kinase Inhibitors
  • Pyridines
  • Doxorubicin
  • NADH Dehydrogenase
  • SB 203580