Mitochondrial NAD kinase in health and disease

• Published in: Redox biology Vol. 60; p. 102613
• Main Authors: Zhang, Ren, Zhang, Kezhong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2023; Elsevier
• Subjects: Animals; Antioxidation; from the Special Issue on Intersection between metabolism and redox biology in health and disease; Edited by Dr. Bradford Guy Hill and Dr. Rakesh Patel; Humans; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; MNADK; NAD; NADK; NADK2; NADP; NADP - metabolism; Phosphotransferases (Alcohol Group Acceptor) - chemistry; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; NAD; NADK2; Mitochondria; MNADK; NADP; Antioxidation; NADK
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2023.102613

Nicotinamide adenine dinucleotide phosphate (NADP), a co-enzyme and an electron carrier, plays crucial roles in numerous biological functions, including cellular metabolism and antioxidation. Because NADP is subcellular-membrane impermeable, eukaryotes compartmentalize NAD kinases (NADKs), the NADP biosynthetic enzymes. Mitochondria are fundamental organelles for energy production through oxidative phosphorylation. Ten years after the discovery of the mitochondrial NADK (known as MNADK or NADK2), a significant amount of knowledge has been obtained regarding its functions, mechanism of action, human biology, mouse models, crystal structures, and post-translation modifications. NADK2 phosphorylates NAD(H) to generate mitochondrial NADP(H). NADK2-deficient patients suffered from hyperlysinemia, elevated plasma C10:2-carnitine (due to the inactivity of relevant NADP-dependent enzymes), and neuronal development defects. Nadk2-deficient mice recapitulate key features of NADK2-deficient patients, including metabolic and neuronal abnormalities. Crystal structures of human NADK2 show a dimer, with the NADP+-binding site located at the dimer interface. NADK2 activity is highly regulated by post-translational modifications, including S188 phosphorylation, K76 and K304 acetylation, and C193 S-nitrosylation; mutations in each site affect NADK2 activity and function. In mice, hepatic Nadk2 functions as a major metabolic regulator upon increased energy demands by regulating sirtuin 3 activity and fatty acid oxidation. Hopefully, future research on NADK2 will not only elucidate its functional roles in health and disease but will also pave the way for novel therapeutics for both rare and common diseases, including NADK2 deficiency and metabolic syndrome. [Display omitted] •NADK2 phosphorylates NAD(H) to generate mitochondrial NADP(H).•NADK2-deficient patients suffer from neurometabolic disorders.•Nadk2-deficient mice recapitulate key features of NADK2-deficient patients.•NADP-binding site at the dimer interface shown by NADK2 crystal structures.•NADK2 activity is highly regulated by post-translational modifications.