Biogerontology

, Volume 13, Issue 5, pp 525–536

Cytosolic malate dehydrogenase regulates senescence in human fibroblasts

  • Seung-Min Lee
  • So Hee Dho
  • Sung-Kyu Ju
  • Jin-Soo Maeng
  • Jeong-Yoon Kim
  • Ki-Sun Kwon
Research Article

DOI: 10.1007/s10522-012-9397-0

Cite this article as:
Lee, SM., Dho, S.H., Ju, SK. et al. Biogerontology (2012) 13: 525. doi:10.1007/s10522-012-9397-0

Abstract

Carbohydrate metabolism changes during cellular senescence. Cytosolic malate dehydrogenase (MDH1) catalyzes the reversible reduction of oxaloacetate to malate at the expense of reduced nicotinamide adenine dinucleotide (NADH). Here, we show that MDH1 plays a critical role in the cellular senescence of human fibroblasts. We observed that the activity of MDH1 was reduced in old human dermal fibroblasts (HDFs) [population doublings (PD) 56], suggesting a link between decreased MDH1 protein levels and aging. Knockdown of MDH1 in young HDFs (PD 20) and the IMR90 human fibroblast cell line resulted in the appearance of significant cellular senescence features, including senescence-associated β-galactosidase staining, flattened and enlarged morphology, increased population doubling time, and elevated p16INK4A and p21CIP1 protein levels. Cytosolic NAD/NADH ratios were decreased in old HDFs to the same extent as in MDH1 knockdown HDFs, suggesting that cytosolic NAD depletion is related to cellular senescence. We found that AMP-activated protein kinase, a sensor of cellular energy, was activated in MDH1 knockdown cells. We also found that sirtuin 1 (SIRT1) deacetylase, a controller of cellular senescence, was decreased in MDH1 knockdown cells. These results indicate that the decrease in MDH1 and subsequent reduction in NAD/NADH ratio, which causes SIRT1 inhibition, is a likely carbohydrate metabolism-controlled cellular senescence mechanism.

Keywords

MDH1SenescenceNAD/NADHAMPKSIRT1

Abbreviations

MDH1

Cytosolic malate dehydrogenase

MDH2

Mitochondrial malate dehydrogenase

NAD

Nicotinamide adenine dinucleotide

NADH

Reduced nicotinamide adenine dinucleotide

AMPK

AMP-activated protein kinase

SIRT1

Sirtuin (silent mating type information regulation 2 homolog) 1

HIC1

Hypermethylated in cancer 1

HDFs

Human dermal fibroblasts

PD

Population doublings

ROS

Reactive oxygen species

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Seung-Min Lee
    • 1
    • 3
  • So Hee Dho
    • 1
  • Sung-Kyu Ju
    • 1
  • Jin-Soo Maeng
    • 2
  • Jeong-Yoon Kim
    • 3
  • Ki-Sun Kwon
    • 1
  1. 1.Laboratory of Cell Signaling, Aging Research CenterKorea Research Institute of Bioscience and Biotechnology (KRIBB)DaejeonSouth Korea
  2. 2.Bio-Nanotechnology Research CenterKorea Food Research Institute (KFRI)SeongnamSouth Korea
  3. 3.Department of Microbiology and Molecular Biology, College of Bioscience and BiotechnologyChungnam National UniversityDaejeonSouth Korea