Deficiency of Nicotinamide Mononucleotide Adenylyltransferase 3 (Nmnat3) Causes Hemolytic Anemia by Altering the Glycolytic Flow in Mature Erythrocytes

Hikosaka, Keisuke; Ikutani, Masashi; Shito, Masayuki; Kazuma, Kohei; Gulshan, Maryam; Nagai, Yoshinori; Takatsu, Kiyoshi; Konno, Katsuhiro; Tobe, Kazuyuki; Kanno, Hitoshi; Nakagawa, Takashi

doi:10.1074/jbc.m114.554378

Cited by 73 publications

(92 citation statements)

References 63 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, NMNAT2 is mostly located in the cytosol and Golgi apparatus (Berger et al, 2005; Yalowitz et al, 2004). Finally, NMNAT3 is highly expressed in erythrocytes with a moderate expression in skeletal muscle and heart, and has been identified in both cytosolic and mitochondrial compartments, with cell/tissue specific subcellular localization patterns (Berger et al, 2005; Felici et al, 2013; Hikosaka et al, 2014; Zhang et al, 2003). The possible implications of the subcellular localization of NMNAT enzymes will be discussed in section 2.3.…”

Section: Introductionmentioning

confidence: 99%

NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus

2015

View full text Add to dashboard Cite

NAD+ has emerged as a vital cofactor that can rewire metabolism, activate sirtuins and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response. This improved understanding of NAD+ metabolism revived interest in NAD+ boosting strategies to manage a wide spectrum of diseases, ranging from diabetes to cancer. In this review, we summarize how NAD+ metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited.

show abstract

Section: Introductionmentioning

confidence: 99%

NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus

2015

View full text Add to dashboard Cite

show abstract

“…We also found that most endogenous Nmnat3 proteins reside in the cytoplasm (Hikosaka et al., 2014; Yamamoto et al., 2016), although several reports claim that Nmnat3 is present in the mitochondria (Nikiforov et al., 2011; VanLinden et al., 2015). However, we also reported that overexpression of Nmnat3 in HeLa cells encouraged localization of Nmnat3 in mitochondria (Hikosaka et al., 2014). Thus, we examined whether overexpression of Nmnat3 contributes to mitochondrial NAD levels in Nmnat3 Tg mice.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, Nmnat3 has been found in the mitochondria and is widely associated with mitochondrial NAD biosynthesis (Berger et al., 2005; Nikiforov et al., 2011; VanLinden et al., 2015). Although Nmnat3 deficiencies in mice caused no obvious changes in mitochondrial NAD levels, suggesting redundancy between mammalian Nmnat isozymes (Hikosaka et al., 2014; Yamamoto et al., 2016), overexpression of Nmnat3 in human cultured cells reportedly contributed to mitochondrial NAD synthesis (Nikiforov et al., 2011). These data suggest that overexpression of Nmnat3 can increase mitochondrial NAD levels and stimulate mitochondrial metabolism in vivo.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

et al. 2018

Self Cite

View full text Add to dashboard Cite

SummaryNicotinamide adenine dinucleotide (NAD) is an important cofactor that regulates various biological processes, including metabolism and gene expression. As a coenzyme, NAD controls mitochondrial respiration through enzymes of the tricarboxylic acid (TCA) cycle, β‐oxidation, and oxidative phosphorylation and also serves as a substrate for posttranslational protein modifications, such as deacetylation and ADP‐ribosylation by sirtuins and poly(ADP‐ribose) polymerase (PARP), respectively. Many studies have demonstrated that NAD levels decrease with aging and that these declines cause various aging‐associated diseases. In contrast, activation of NAD metabolism prevents declines in NAD levels during aging. In particular, dietary supplementation with NAD precursors has been associated with protection against age‐associated insulin resistance. However, it remains unclear which NAD synthesis pathway is important and/or efficient at increasing NAD levels in vivo. In this study, Nmnat3 overexpression in mice efficiently increased NAD levels in various tissues and prevented aging‐related declines in NAD levels. We also demonstrated that Nmnat3‐overexpressing (Nmnat3 Tg) mice were protected against diet‐induced and aging‐associated insulin resistance. Moreover, in skeletal muscles of Nmnat3 Tg mice, TCA cycle activity was significantly enhanced, and the energy source for oxidative phosphorylation was shifted toward fatty acid oxidation. Furthermore, reactive oxygen species (ROS) generation was significantly suppressed in aged Nmnat3 Tg mice. Interestingly, we also found that concentrations of the NAD analog nicotinamide guanine dinucleotide (NGD) were dramatically increased in Nmnat3 Tg mice. These results suggest that Nmnat3 overexpression improves metabolic health and that Nmnat3 is an attractive therapeutic target for metabolic disorders that are caused by aging.

show abstract

“…7, 8). Of note, NMNAT3 knockout mice appear viable,41 although it is not yet known whether these mice have abnormalities in neuronal development or survival under basal or injurious conditions. Lastly, increases in endogenous NMNAT3 24 h following H‐I were primarily observed in the hypoxic side of the pup brain.…”

Section: Discussionmentioning

confidence: 99%

NMNAT3 is protective against the effects of neonatal cerebral hypoxia‐ischemia

Galindo

Greenberg

Araki

et al. 2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveTo determine whether the NAD+ biosynthetic protein, nicotinamide mononucleotide adenylyltransferase‐3 (NMNAT3), is a neuroprotective inducible enzyme capable of decreasing cerebral injury after neonatal hypoxia‐ischemia (H‐I) and reducing glutamate receptor‐mediated excitotoxic neurodegeneration of immature neurons.MethodsUsing NMNAT3‐overexpressing mice we investigated whether increases in brain NMNAT3 reduced cerebral tissue loss following H‐I. We then employed biochemical methods from injured neonatal brains to examine the inducibility of NMNAT3 and the mechanism of NMNAT3‐dependent neuroprotection. Using AAV8‐mediated vectors for in vitro neuronal NMNAT3 knockdown, we then examine the endogenous role of this protein on immature neuronal survival prior and following NMDA receptor‐mediated excitotoxicity.ResultsNMNAT3 mRNA and protein levels increased after neonatal H‐I. In addition, NMNAT3 overexpression decreased cortical and hippocampal tissue loss 7 days following injury. We further show that the NMNAT3 neuroprotective mechanism involves a decrease in calpastatin degradation, and a decrease in caspase‐3 activity and calpain‐mediated cleavage. Conversely, NMNAT3 knockdown of cortical and hippocampal neurons in vitro caused neuronal degeneration and increased excitotoxic cell death. The neurodegenerative effects of NMNAT3 knockdown were counteracted by exogenous upregulation of NMNAT3.ConclusionsOur observations provide new insights into the neuroprotective mechanisms of NMNATs in the injured developing brain, adding NMNAT3 as an important neuroprotective enzyme in neonatal H‐I via inhibition of apoptotic and necrotic neurodegeneration. Interestingly, we find that endogenous NMNAT3 is an inducible protein important for maintaining the survival of immature neurons. Future studies aimed at uncovering the mechanisms of NMNAT3 upregulation and neuroprotection may offer new therapies against the effects of hypoxic‐ischemic encephalopathy.

show abstract

Deficiency of Nicotinamide Mononucleotide Adenylyltransferase 3 (Nmnat3) Causes Hemolytic Anemia by Altering the Glycolytic Flow in Mature Erythrocytes

Cited by 73 publications

References 63 publications

NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus

NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

NMNAT3 is protective against the effects of neonatal cerebral hypoxia‐ischemia

Contact Info

Product

Resources

About