NDLI: Cytosolic malate dehydrogenase regulates senescence in human fibroblasts

Content Provider	Springer Nature Link
Author	Lee, Seung Min Dho, So Hee Ju, Sung Kyu Maeng, Jin Soo Kim, Jeong Yoon Kwon, Ki Sun
Copyright Year	2012
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.
Starting Page	525
Ending Page	536
Page Count	12
File Format	PDF
ISSN	13895729
Journal	Biogerontology
Volume Number	13
Issue Number	5
e-ISSN	15736768
Language	English
Publisher	Springer Netherlands
Publisher Date	2012-09-13
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	MDH1 Senescence NAD/NADH AMPK SIRT1 Cell Biology Geriatrics/Gerontology Developmental Biology
Content Type	Text
Resource Type	Article
Subject	Aging Gerontology Geriatrics and Gerontology

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