Nmnat3, or nicotinamide mononucleotide adenylyltransferase 3, is an enzyme catalyzing NAD+ synthesis, a crucial cofactor associated with numerous biological processes maintaining homeostasis in all living organisms [1,2,3,4,5,6,7,8]. It has been proposed to be involved in de novo and salvage pathways related to NAD+ biosynthesis and is thought to be associated with mitochondrial function, though its exact sub-cellular localization and role in mitochondrial NAD+ synthesis are still under investigation [4,8].

In Nmnat3-KO mice, Nmnat3 deficiency causes splenomegaly and hemolytic anemia due to reduced NAD levels in mature erythrocytes, as the glycolysis pathway in these erythrocytes is blocked at the glyceraldehyde 3-phosphate dehydrogenase step, leading to a glycolysis stall and a shift to the pentose phosphate pathway [8]. Additionally, Nmnat3-deficient mice show exacerbated malaria infection, as the NAD+ levels in malaria-infected Nmnat3-deficient red blood cells increase and the glycolytic flow enhances to support malarial parasite growth, causing death [1]. In contrast, overexpression of Nmnat3 in mice efficiently increases NAD levels in various tissues, prevents aging-related declines in NAD levels, and protects against diet-induced and aging-associated insulin resistance. In skeletal muscles of these mice, TCA cycle activity is enhanced, and ROS generation is suppressed [7].

In conclusion, Nmnat3 plays a critical role in maintaining the NAD+ pool, especially in mature erythrocytes, as demonstrated by Nmnat3-KO mouse models. These models also reveal its implications in diseases such as hemolytic anemia, malaria, and age-associated insulin resistance, highlighting its potential as a therapeutic target for related metabolic disorders [1,7,8].

References:

1. Mahmood, Arshad, Yaku, Keisuke, Hikosaka, Keisuke, Kobayashi, Fumie, Nakagawa, Takashi. 2022. Nmnat3 deficiency in hemolytic anemia exacerbates malaria infection. In Biochemical and biophysical research communications, 637, 58-65. doi:10.1016/j.bbrc.2022.11.003. https://pubmed.ncbi.nlm.nih.gov/36375251/

2. Cambronne, Xiaolu A, Stewart, Melissa L, Kim, DongHo, Cohen, Michael S, Goodman, Richard H. . Biosensor reveals multiple sources for mitochondrial NAD⁺. In Science (New York, N.Y.), 352, 1474-7. doi:10.1126/science.aad5168. https://pubmed.ncbi.nlm.nih.gov/27313049/

3. Galindo, Rafael, Banks Greenberg, Marianne, Araki, Toshiyuki, Milbrandt, Jeffrey, Holtzman, David M. 2017. NMNAT3 is protective against the effects of neonatal cerebral hypoxia-ischemia. In Annals of clinical and translational neurology, 4, 722-738. doi:10.1002/acn3.450. https://pubmed.ncbi.nlm.nih.gov/29046881/

4. Yamamoto, Masashi, Hikosaka, Keisuke, Mahmood, Arshad, Inohara, Hidenori, Nakagawa, Takashi. 2016. Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo. In PloS one, 11, e0147037. doi:10.1371/journal.pone.0147037. https://pubmed.ncbi.nlm.nih.gov/26756334/

5. Wang, Tao, Zhang, Fei, Peng, Wuxun, Li, Yanlin, Gong, Yuekun. . Overexpression of NMNAT3 improves mitochondrial function and enhances antioxidative stress capacity of bone marrow mesenchymal stem cells via the NAD+-Sirt3 pathway. In Bioscience reports, 42, . doi:10.1042/BSR20211005. https://pubmed.ncbi.nlm.nih.gov/34981121/

6. Yue, Zhongbao, Ma, Yunzi, You, Jia, Chen, Shaorui, Liu, Peiqing. 2016. NMNAT3 is involved in the protective effect of SIRT3 in Ang II-induced cardiac hypertrophy. In Experimental cell research, 347, 261-73. doi:10.1016/j.yexcr.2016.07.006. https://pubmed.ncbi.nlm.nih.gov/27423420/

7. Gulshan, Maryam, Yaku, Keisuke, Okabe, Keisuke, Tobe, Kazuyuki, Nakagawa, Takashi. 2018. Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age-associated insulin resistance. In Aging cell, 17, e12798. doi:10.1111/acel.12798. https://pubmed.ncbi.nlm.nih.gov/29901258/

8. Hikosaka, Keisuke, Ikutani, Masashi, Shito, Masayuki, Kanno, Hitoshi, Nakagawa, Takashi. 2014. Deficiency of nicotinamide mononucleotide adenylyltransferase 3 (nmnat3) causes hemolytic anemia by altering the glycolytic flow in mature erythrocytes. In The Journal of biological chemistry, 289, 14796-811. doi:10.1074/jbc.M114.554378. https://pubmed.ncbi.nlm.nih.gov/24739386/