Regulation of replicative senescence by NADP+-dependent isocitrate dehydrogenase

In Sup Kil, Tae Lin Huh, Young Sup Lee, You Mie Lee, Jeen Woo Park

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

The free radical hypothesis of aging postulates that senescence is due to an accumulation of cellular oxidative damage, caused largely by reactive oxygen species that are produced as by-products of normal metabolic processes. Recently, we demonstrated that the control of cytosolic and mitochondrial redox balance and the cellular defense against oxidative damage is one of the primary functions of cytosolic (IDPc) and mitochondrial NADP+-dependent isocitrate dehydrogenase (IDPm) by supplying NADPH for antioxidant systems. In this paper, we demonstrate that modulation of IDPc or IDPm activity in IMR-90 cells regulates cellular redox status and replicative senescence. When we examined the regulatory role of IDPc and IDPm against the aging process with IMR-90 cells transfected with cDNA for IDPc or IDPm in sense and antisense orientations, a clear inverse relationship was observed between the amount of IDPc or IDPm expressed in target cells and their susceptibility to senescence, which was reflected by changes in replicative potential, cell cycle, senescence-associated β-galactosidase activity, expression of p21 and p53, and morphology of cells. Furthermore, lipid peroxidation, oxidative DNA damage, and intracellular peroxide generation were higher and cellular redox status shifted to a prooxidant condition in the cell lines expressing the lower level of IDPc or IDPm. The results suggest that IDPc and IDPm play an important regulatory role in cellular defense against oxidative stress and in the senescence of IMR-90 cells.

Original languageEnglish
Pages (from-to)110-119
Number of pages10
JournalFree Radical Biology and Medicine
Volume40
Issue number1
DOIs
StatePublished - 1 Jan 2006

Keywords

  • Aging
  • Antioxidant enzyme
  • Free radicals
  • IMR-90
  • Oxidative stress
  • Redox status

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