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Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo

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....

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Autores principales: Yamamoto, Masashi, Hikosaka, Keisuke, Mahmood, Arshad, Tobe, Kazuyuki, Shojaku, Hideo, Inohara, Hidenori, Nakagawa, Takashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710499/
https://www.ncbi.nlm.nih.gov/pubmed/26756334
http://dx.doi.org/10.1371/journal.pone.0147037
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author Yamamoto, Masashi
Hikosaka, Keisuke
Mahmood, Arshad
Tobe, Kazuyuki
Shojaku, Hideo
Inohara, Hidenori
Nakagawa, Takashi
author_facet Yamamoto, Masashi
Hikosaka, Keisuke
Mahmood, Arshad
Tobe, Kazuyuki
Shojaku, Hideo
Inohara, Hidenori
Nakagawa, Takashi
author_sort Yamamoto, Masashi
collection PubMed
description 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.
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spelling pubmed-47104992016-01-26 Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo Yamamoto, Masashi Hikosaka, Keisuke Mahmood, Arshad Tobe, Kazuyuki Shojaku, Hideo Inohara, Hidenori Nakagawa, Takashi PLoS One Research Article 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. Public Library of Science 2016-01-12 /pmc/articles/PMC4710499/ /pubmed/26756334 http://dx.doi.org/10.1371/journal.pone.0147037 Text en © 2016 Yamamoto et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Yamamoto, Masashi
Hikosaka, Keisuke
Mahmood, Arshad
Tobe, Kazuyuki
Shojaku, Hideo
Inohara, Hidenori
Nakagawa, Takashi
Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo
title Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo
title_full Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo
title_fullStr Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo
title_full_unstemmed Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo
title_short Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo
title_sort nmnat3 is dispensable in mitochondrial nad level maintenance in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710499/
https://www.ncbi.nlm.nih.gov/pubmed/26756334
http://dx.doi.org/10.1371/journal.pone.0147037
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