Nicotinamide adenine dinucleotide kinase 2, mitochondrial (NADK2), is a mitochondrial enzyme encoded by the human NADK2 gene. In eukaryotes it maintains the mitochondrial NADP(H) pool by phosphorylating NAD+ and NADH.[5] NADPH plays a central role in mitochondrial metabolism by providing reducing power for protection against oxidative stress and for mitochondrial fatty acid synthesis (mtFAS), proline biosynthesis, lysine degradation, and the beta oxidation of polyunsaturated fatty acids.[6][5] NADK2 was identified in humans by Ohashi et al. in 2012, more than a decade after its cytosolic counterpart, NADK1.[5] Mutations in the NADK2 gene cause an autosomal recessive disorder known as NADK2 deficiency.[7]
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| Aliases | NADK2, C5orf33, MNADK, NADKD1, DECRD, NAD kinase 2, mitochondrial | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 615787; MGI: 1915896; HomoloGene: 14638; GeneCards: NADK2; OMA:NADK2 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Reaction
editStructure
editNADK2 differs from other NAD kinases by containing an additional structural insert that alters its assembly.[8] While most NAD kinases form tetramers, NADK2 exists as a stable homodimer.[8] As a result, its activity remains relatively constant and does not increase upon oligomerization, unlike other NAD kinases.[8]
Function
editBecause NADP(H), which exists in oxidized (NADP+) and reduced (NADPH) forms, cannot cross the mitochondrial membrane, eukaryotic cells maintain separate cytosolic and mitochondrial NADP(H) pools through dedicated NAD kinases.[5] In mitochondria, NADK2 catalyzes the phosphorylation of NAD+ to NADP+ and, notably, can also phosphorylate NADH to NADPH.[5] NADP+ generated by NADK2 or by NADPH oxidation is reduced to NADPH by enzymes including NNT, GLUD1, ME2, ALDH1L2, and IDH2.[6] By contrast, using NADH as a substrate allows NADK2 to generate mitochondrial NADPH directly and rapidly, albeit at the expense of ATP.[9] These reactions maintain a predominantly reduced NADPH pool that provides electrons for central mitochondrial processes.[6] As mitochondria are a major source of oxidative stress due to reactive oxygen species (ROS) generated by the electron transport chain, they depend on NADPH for antioxidant protection.[10] Mitochondrial NADPH fulfills this role by regenerating glutathione and thioredoxin via glutathione reductase and thioredoxin reductase, respectively, thereby supporting the detoxification of ROS.[11] NADPH also fuels mitochondrial fatty acid synthesis (mtFAS) through enzymes such as MECR, contributing to protein lipoylation as well as mitochondrial translation, electron transport chain assembly, and citric acid cycle function.[6] In addition, NADPH is used by enzymes including pyrroline-5-carboxylate synthase (P5CS) in proline biosynthesis, alpha-aminoadipic semialdehyde synthase (AASS) in lysine degradation, and 2,4-dienoyl-CoA reductase 1 (DECR) in the auxiliary pathway of mitochondrial beta oxidation of polyunsaturated fatty acids.[5]
Clinical significance
editRecessive mutations in NADK2 cause NADK2 deficiency, an inherited metabolic disorder characterized by neurological symptoms including hypotonia, developmental delay, ataxia, and encephalopathy.[7] Affected individuals also show metabolic abnormalities, including hyperlysinemia and impaired fat oxidation with elevated C10:2-carnitine levels, consistent with secondary 2,4-dienoyl-CoA reductase deficiency.[5]
Cancer cells are exposed to elevated oxidative stress and are consequently highly dependent on mitochondrial NADPH to maintain redox homeostasis.[9] NADK2 is essential for mitochondrial NADPH production and has therefore been proposed as a potential target to increase oxidative stress and sensitize cancer cells to apoptosis.[9] A lack of NADK2 additionally impairs proline biosynthesis, rendering cancer cells dependent on exogenous proline for proliferation.[12]
NADK2 has been linked to Alzheimer's disease.[13] Tau oligomers upregulate NADK2 in human neurons, leading to increased mitochondrial NADPH production, which in turn increases LRP1 expression and promotes tau uptake, creating a self-reinforcing cycle.[13]
References
edit- 1 2 3 GRCh38: Ensembl release 89: ENSG00000152620 – Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022253 – Ensembl, May 2017
- ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- 1 2 3 4 5 6 7 8 9 Zhang R, Zhang K (April 2023). "Mitochondrial NAD kinase in health and disease". Redox Biology. 60 102613. doi:10.1016/j.redox.2023.102613. PMC 9873681. PMID 36689815.
- 1 2 3 4 Wedan RJ, Nowinski SM (July 2025). "Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism". Cell Chemical Biology. 32 (7): 902–904. doi:10.1016/j.chembiol.2025.06.006. PMC 12507123. PMID 40680726.
- 1 2 Murray GC, Bais P, Hatton CL, Tadenev AL, Hoffmann BR, Stodola TJ, et al. (November 2022). "Mouse models of NADK2 deficiency analyzed for metabolic and gene expression changes to elucidate pathophysiology". Human Molecular Genetics. 31 (23): 4055–4074. doi:10.1093/hmg/ddac151. PMC 9703942. PMID 35796562.
- 1 2 3 Du J, Estrella M, Solorio-Kirpichyan K, Jeffrey PD, Korennykh A (June 2022). "Structure of human NADK2 reveals atypical assembly and regulation of NAD kinases from animal mitochondria". Proceedings of the National Academy of Sciences of the United States of America. 119 (26) e2200923119. Bibcode:2022PNAS..11900923D. doi:10.1073/pnas.2200923119. PMC 9245612. PMID 35733246.
- 1 2 3 Ciccarese F, Ciminale V (2017). "Escaping Death: Mitochondrial Redox Homeostasis in Cancer Cells". Frontiers in Oncology. 7 117. doi:10.3389/fonc.2017.00117. PMC 5465272. PMID 28649560.
- ↑ Kim H, Fu Z, Yang Z, Song Z, Shamsa EH, Yumnamcha T, et al. (October 2022). "The mitochondrial NAD kinase functions as a major metabolic regulator upon increased energy demand". Molecular Metabolism. 64 101562. doi:10.1016/j.molmet.2022.101562. PMC 9403569. PMID 35944895.
- ↑ Moon SJ, Dong W, Stephanopoulos GN, Sikes HD (September 2020). "Oxidative pentose phosphate pathway and glucose anaplerosis support maintenance of mitochondrial NADPH pool under mitochondrial oxidative stress". Bioengineering & Translational Medicine. 5 (3) e10184. doi:10.1002/btm2.10184. PMC 7510474. PMID 33005744.
- ↑ Kim D, Kesavan R, Ryu K, Dey T, Marckx A, Menezes C, et al. (May 2025). "Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism". Nature Cell Biology. 27 (5): 790–800. doi:10.1038/s41556-025-01655-4. PMC 12331256. PMID 40258949.
- 1 2 Pardo E, Kim T, Wallrabe H, Zengeler KE, Sagar VK, Mingledorff G, et al. (2024-11-01). "Mitochondrial NADK2-dependent NADPH controls Tau oligomer uptake in human neurons". bioRxiv 10.1101/2024.10.31.621392.