huMTARC1/huMTARC2 Mouse
Product Name
huMTARC1/huMTARC2 Mouse
Product ID
C001912
Strain Name
C57BL/6NCya-Mtarc1tm1(hMTARC1)Mtarc2tm1(hMTARC2)/Cya
Backgroud
C57BL/6NCya
Status
When using this mouse strain in a publication, please cite “huMTARC1/huMTARC2 Mouse (Catalog C001912) were purchased from Cyagen.”
Product Type
Age
Genotype
Sex
Quantity
Gene Name
MTARC2 & MTARC1
Gene Alias
MARC2, MOSC2, MARC1, MOSC1
NCBI ID
Chromosome
Chr 1 (Human), Chr 1 (Human)
MGI ID
Datasheet
Strain Description
MTARC1 and MTARC2 encode the mitochondrial amidoxime-reducing components 1 and 2 (mARC1/mARC2), two paralogous molybdenum-containing enzymes anchored to the outer mitochondrial membrane that form a three-component system with cytochrome b5 (CYB5B) and NADH-cytochrome b5 reductase 3 (CYB5R3) to catalyze the reduction of N-oxygenated compounds [1]. These genes are widely expressed, with particularly high levels in liver hepatocytes, as well as in other tissues like adipose and various fetal/adult organs; the encoded proteins function primarily in N-reduction of substrates including amidoximes (for prodrug activation), nitrite, Nω-hydroxy-L-arginine (NOHA), N-hydroxyurea, and hydrogen peroxide, contributing to detoxification, nitric oxide homeostasis, lipid metabolism regulation, and mitochondrial redox balance [2-3]. MTARC1 has gained significant attention due to a common protective missense variant (p.A165T) strongly associated with reduced liver fat, lower plasma lipids and liver enzymes (e.g., ALT), decreased risk of metabolic dysfunction-associated steatotic liver disease (MASLD/MASH), all-cause cirrhosis, and liver-related mortality; genetic and experimental knockdown of MTARC1 in hepatocytes reduces steatosis, fibrosis, and inflammation in mouse models, positioning mARC1 inhibition (e.g., via liver-specific siRNA) as a promising therapeutic strategy for MASH [4-5]. MTARC2 shares overlapping substrate specificities and roles but appears less central to the liver disease associations compared to MTARC1 [6].
The huMTARC1/huMTARC2 mouse is a dual-gene humanized model generated via gene editing. The sequences from upstream of exon 1 of the mouse Mtarc2 gene to downstream of exon 7 of the mouse Mtarc1 gene were replaced with the sequences from upstream of exon 1 of the human MTARC2 gene to downstream of exon 7 of the human MTARC1 gene. This model is applicable for evaluating drug efficacy in MASLD/MASH, elucidating mechanisms of hepatic lipid metabolism, conducting PK/PD and reductase activity studies, and facilitating the development of MTARC1/MTARC2-targeted therapeutics.
Reference
Struwe MA, Scheidig AJ, Clement B. The mitochondrial amidoxime reducing component-from prodrug-activation mechanism to drug-metabolizing enzyme and onward to drug target. J Biol Chem. 2023 Nov;299(11):105306.
Guo Y, Gao Z, LaGory EL, Kristin LW, Gupte J, Gong Y, Rardin MJ, Liu T, Nguyen TT, Long J, Hsu YH, Murray JK, Lade J, Jackson S, Zhang J. Liver-specific mitochondrial amidoxime-reducing component 1 (Mtarc1) knockdown protects the liver from diet-induced MASH in multiple mouse models. Hepatol Commun. 2024 May 2;8(5):e0419.
Hou W, Watson C, Cecconie T, Bolaki MN, Brady JJ, Lu Q, Gatto GJ Jr, Day TA. Biochemical and functional characterization of the p.A165T missense variant of mitochondrial amidoxime-reducing component 1. J Biol Chem. 2024 Jun;300(6):107353.
Coyne ES, Nie Y, Lee D, Pandovski S, Yang T, Zhou H, Rosahl TW, Carballo-Jane E, Abdurrachim D, Zhou Y, Hendra C, Ali AAB, Meyers S, Blumenschein W, Gongol B, Liu Y, Zhou Y, Talukdar S. Loss of mitochondrial amidoxime-reducing component 1 (mARC1) prevents disease progression by reducing fibrosis in multiple mouse models of chronic liver disease. Hepatol Commun. 2025 Feb 10;9(2):e0637.
Lewis LC, Chen L, Hameed LS, Kitchen RR, Maroteau C, Nagarajan SR, Norlin J, Daly CE, Szczerbinska I, Hjuler ST, Patel R, Livingstone EJ, Durrant TN, Wondimu E, BasuRay S, Chandran A, Lee WH, Hu S, Gilboa B, Grandi ME, Toledo EM, Erikat AHA, Hodson L, Haynes WG, Pursell NW, Coppieters K, Fleckner J, Howson JMM, Andersen B, Ruby MA. Hepatocyte mARC1 promotes fatty liver disease. JHEP Rep. 2023 Feb 3;5(5):100693.
Klopp C, Zhang X, Campbell MK, Kvaskoff D, Struwe MA, Warren CR, Bajrami B, Scheidig AJ, Jones AK, Clement B. mARC1 Is the Main Contributor to Metabolic Reduction of N-Hydroxyurea. J Med Chem. 2024 Oct 24;67(20):18090-18097.
Strain Strategy
The sequences from upstream of exon 1 of the mouse Mtarc2 gene to downstream of exon 7 of the mouse Mtarc1 gene were replaced with the sequences from upstream of exon 1 of the human MTARC2 gene to downstream of exon 7 of the human MTARC1 gene. The expression of mouse Mir1981 will be affected by the deletion of this KO region.
Figure 1. Gene editing strategy for huMTARC1/huMTARC2 mice.
Application Area
Screening, development, and safety assessment of MTARC1/MTARC2-targeted therapeutics;
Evaluation of drug efficacy for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD/MASH);
Research on hepatic lipid metabolism and related metabolic disorders;
PK/PD and reductase activity studies;
Research on tumor metabolism and the regulation of drug sensitivity;
Studies on risk factors associated with cardiovascular disease.
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