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Title 

Cytosolic malate dehydrogenase regulates senescence in human fibroblasts

Authors 

Seung-Min LeeSo Hee DhoS K JuJ S MaengJ Y KimKi Sun Kwon

Publisher 

Springer Verlag (Germany)

Issue Date 

2012

Citation 

Biogerontology, vol. 13, no. 5, pp. 525-536

Keywords 

AMPKMDH1NAD/NADHSenescenceSIRT1

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 p16 INK4A and p21 CIP1 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.

ISSN 

1389-5729

Link 

http://dx.doi.org/10.1007/s10522-012-9397-0

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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