Nmrk2, also known as nicotinamide riboside kinase 2 or muscle integrin binding protein (MIBP), is involved in nicotinamide adenine dinucleotide (NAD) coenzyme biosynthesis. It phosphorylates the nicotinamide riboside precursor and is crucial for maintaining NAD homeostasis. NMRK2 has been associated with pathways related to energy metabolism, muscle function, and cell growth. Gene knockout mouse models have been valuable in studying its functions [2,3,5].

In Xp11.2 translocation renal cell carcinoma (tRCC), NMRK2 is specifically upregulated, and the TFE3 fusion protein binds to its promoter leading to this upregulation. Knockdown of NMRK2 in Xp11.2 tRCC weakens mitochondrial respiration, and supplementation with NAD+ precursors can rescue phenotypes induced by its knockdown, suggesting it promotes cancer progression [1,4].

In dilated cardiomyopathy (DCM), Nmrk2 is upregulated, and Nmrk2 -/- mice develop a DCM-like phenotype with aging, showing eccentric remodeling, decline in ejection fraction, and reduced myocardial NAD levels, indicating its importance in cardiac function and NAD levels during aging [3].

In skeletal muscle, aged Nmrk2 -/- mice show an altered response to endurance exercise training, with changes in gene expression related to fatty acid catabolism in the heart and induction of Myh7 in skeletal muscle [5].

In summary, NMRK2 is essential for energy metabolism, playing key roles in maintaining cardiac function during aging and promoting the progression of Xp11.2 tRCC. The study of Nmrk2 knockout mouse models has provided significant insights into its functions in these disease-related processes, highlighting its potential as a therapeutic target in related diseases.