title: Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo.
abstract: Nicotinamide adenine dinucleotide (NAD) is an essential co-enzyme mediating various enzymatic reactions. Mitochondrial NAD particularly occupies a considerable amount of total NAD in cells, and serves as a co-enzyme in tricarboxylic acid cycle (TCA cycle), β-oxidation, and oxidative phosphorylation. Despite the importance of mitochondrial NAD, its synthesis pathway remains unknown. It has been proposed that NAD synthesis enzyme, Nmnat3, was localized in mitochondria, but its physiological relevance to the metabolism in mitochondria was not fully elucidated. Previously, we have reported that murine Nmnat3 protein was strongly expressed in the cytoplasm of mature erythrocytes, in which mitochondria were absent, and Nmnat3-deficient mice (Nmnat3-KO mice) exhibited splenomegaly and hemolytic anemia due to reduced NAD levels in mature erythrocytes. These results challenged the role of Nmnat3 in mitochondrial NAD synthesis. In this study, we demonstrated that mitochondrial NAD levels in various tissues, except for red blood cells, were unchanged in Nmnat3-KO mice. We also analyzed the metabolites in glycolysis and TCA cycle and found that there were no differences between Nmnat3-KO and WT mice. In addition, the aged Nmnat3-KO mice had comparable NAD levels to that observed in WT mice. Our results indicated that Nmnat3 is dispensable in the maintenance of mitochondrial NAD levels, and that other NAD regulatory pathways may exist in mitochondria.
authors.affiliation: Frontier Research Core for Life Sciences, University of Toyama, Toyama 930-0194, Japan.|Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Frontier Research Core for Life Sciences, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hikosaka
authors.affiliation: Frontier Research Core for Life Sciences, University of Toyama, Toyama 930-0194, Japan.|First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Arshad
authors.initials: A
authors.lastname: Mahmood
authors.affiliation: First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Shojaku
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Inohara
authors.affiliation: Frontier Research Core for Life Sciences, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism*
chemical_list: D009243:NAD; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C000592579:nicotinamide mononucleotide adenylyltransferase 3, mouse