Aldehyde dehydrogenase 1A1 increases NADH levels and promotes tumor growth via glutathione/dihydrolipoic acid-dependent NAD + reduction

// Baiyun Wang 1, 2, 3 , Xue Chen 2 , Zixi Wang 2 , Wei Xiong 3 , Tao Xu 3 , Xinyuan Zhao 3 , Yang Cao 3 , Yanru Guo 2 , Lin Li 3 , She Chen 3 , Song Huang 3 , Xiaodong Wang 3 , Min Fang 2 and Zhirong Shen 3 1 Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing, 100084, China 2 Joint Center for Life Sciences, and School of Life Sciences, Peking University, Beijing, 100871, China 3 National Institute of Biological Sciences, Beijing, 102206, China Correspondence to: Zhirong Shen, email: shenzhirong@nibs.ac.cn Min Fang, email: min.fang@pku.edu.cn Keywords: aldehyde dehydrogenase, lung cancer, glutathione, dihydrolipoic acid, NAD + /NADH ratio Received: December 15, 2016      Accepted: April 07, 2017      Published: May 08, 2017 ABSTRACT Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of the aldehyde dehydrogenase superfamily that oxidizes aldehydes to their corresponding acids, reactions that are coupled to the reduction of NAD + to NADH. We report here that ALDH1A1 can also use glutathione (GSH) and dihydrolipoic acid (DHLA) as electron donors to reduce NAD + to NADH. The GSH/DHLA-dependent NAD + -reduction activity of ALDH1A1 is not affected by the aldehyde dehydrogenase inhibitor or by mutation of the residues in its aldehyde-binding pocket. It is thus a distinct biochemical reaction from the classic aldehyde-dehydrogenase activity catalyzed by ALDH1A1. We also found that the ectopic expression of ALDH1A1 decreased the intracellular NAD + /NADH ratio, while knockout of ALDH1A1 increased the NAD + /NADH ratio. Simultaneous knockout of ALDH1A1 and its isozyme ALDH3A1 in lung cancer cell line NCI-H460 inhibited tumor growth in a xenograft model. Moreover, the ALDH1A1 mutants that retained their GSH/DHLA-dependent NAD + reduction activity but lost their aldehyde-dehydrogenase activity were able to decrease the NAD + /NADH ratio and to rescue the impaired growth of ALDH1A1/3A1 double knockout tumor cells. Collectively, these results suggest that this newly characterized GSH/DHLA-dependent NAD + -reduction activity of ALDH1A1 can decrease cellular NAD + /NADH ratio and promote tumor growth.