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

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.

The mitochondrial deoxyguanosine kinase is required for female fertility in mice

“…In our previous studies, we found that DGUOK deletion affected the assembly of mitochondrial complex I, and robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self-renewal (33,34). We also found DGUOK regulates nicotinamide adenine dinucleotide (NAD + ) biosynthesis independent of the mitochondrial complex I (35) that Dguok deficiency-mediated mitochondria dysfunction plays a key role in aging, which is consistent with previous research (36).…”

“…In our previous studies, we found that DGUOK deletion affected the assembly of mitochondrial complex I, and robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self-renewal(33, 34). We also found DGUOK regulates nicotinamide adenine dinucleotide (NAD + ) biosynthesis independent of the mitochondrial complex I (35). To further investigate the pathophysiological function of DGUOK, we constructed Dguok knockout mice (Fig S1A), in which the second exon of Dguok was completely deleted., and the deletion of which resulted in frame-shift mutation and early termination of translation.…”

Aberrant Expression and Prognostic Potential of IL-37 in Human Lung Adenocarcinoma

“…Increased levels of CXCL14 mRNA have been detected in LUAD biopsies with a micropapillary pattern [ 55 ], and smoking-induced CXCL14 expression in the human airway epithelium has been implicated in chronic obstructive pulmonary disease (COPD)-mediated lung cancer development [ 56 ]. Similarly, NMNAT2 expression was found to be increased in LUAD specimens and correlated negatively with OS of patients, whereas the DGUOK-NMNAT2-NAD+ axis was suggested as a potential therapeutic target for the disease [ 57 ]. Increased expression levels of HLF, shown to promote cell-cycle progression in various cancers [ 58 ], ITGA2 , MUC1 , and DPY19L1 have also been proposed to confer prognostic value for the survival of patients suffering from LUAD malignancies [ 59 , 60 , 61 , 62 , 63 , 64 ].…”

Inhibitors of NAD+ Production in Cancer Treatment: State of the Art and Perspectives

“…Notwithstanding, this osteosarcoma cell line also showed an upregulated NMNAT1 expression in response to DNA damage [108]. Lung adenocarcinoma shows high expression levels of NMNAT2, and the expression of this gene in this type of cancer was found to negatively correlate with patient survival in two different databases [114]. In lung cancer, NMNAT2 expression was shown to be regulated by deoxyguanosine kinase (DGUOK), a critical enzyme for mitochondrial purine metabolism [114].…”