Mitochondrial Deoxyguanosine Kinase Regulates NAD+ Biogenesis Independent of Mitochondria Complex I Activity

Lei Sang; Ying-Jie He; Jiaxin Kang; Hongyi Ye; Weiyu Bai; Xiao-Dong Luo; Jianwei Sun

doi:10.3389/fonc.2020.570656

Mitochondrial Deoxyguanosine Kinase Regulates NAD⁺ Biogenesis Independent of Mitochondria Complex I Activity

Front Oncol. 2020 Dec 18:10:570656. doi: 10.3389/fonc.2020.570656. eCollection 2020.

Authors

Lei Sang¹, Ying-Jie He², Jiaxin Kang¹, Hongyi Ye¹, Weiyu Bai¹, Xiao-Dong Luo², Jianwei Sun¹

Affiliations

¹ State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China.
² Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, China.

Abstract

Overexpression of DGUOK promotes mitochondria oxidative phosphorylation and lung adenocarcinoma progression. However, the role and mechanism of DGUOK in regulation of mitochondria function and lung cancer progression still poorly understood. Here we demonstrated that DGUOK regulated NAD⁺ biogenesis. Depletion of the DGUOK significantly decreased NAD⁺ level. Furthermore, knockout of the DGUOK considerably reduced expression of the NMNAT2, a key molecule controlling NAD⁺ synthesis, at both mRNA and protein levels. Ectopic expression of the NMNAT2 abrogated the effect of knockdown of DGUOK on NAD⁺. Notably, this regulation is independent of DGUOK -mediated mitochondria complex I activity. We also showed that NMNAT2 was highly expressed in lung adenocarcinoma and negatively correlated with the patient overall survival. Our study suggested that DGUOK regulates NAD⁺ in a NMNAT2 dependent manner and DGUOK-NMNAT2-NAD⁺ axis could be a potential therapeutic target in lung adenocarcinoma.

Keywords: NAD+; NMNAT2; deoxyguanosine kinase; lung adenocarcinoma; mitochondria complex I.