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A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

ABSTRACT: Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.

SUBMITTER: Emdin CA

PROVIDER: S-EPMC7200007 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Correction: A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

Project description:[This corrects the article DOI: 10.1371/journal.pgen.1008629.].

| S-EPMC8023447 | biostudies-literature

Divergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse

Project description:Recent human genome-wide association studies have identified common missense variants in MARC1, p.Ala165Thr and p.Met187Lys, associated with lower hepatic fat, reduction in liver enzymes and protection from most causes of cirrhosis. Using an exome-wide association study we recapitulated earlier MARC1 p.Ala165Thr and p.Met187Lys findings in 540,000 individuals from five ancestry groups. We also discovered novel rare putative loss of function variants in MARC1 with a phenotype similar to MARC1 p.Ala165Thr/p.Met187Lys variants. In vitro studies of recombinant human MARC1 protein revealed Ala165Thr substitution causes protein instability and aberrant localization in hepatic cells, suggesting MARC1 inhibition or deletion may lead to hepatoprotection. Following this hypothesis, we generated Marc1 knockout mice and evaluated the effect of Marc1 deletion on liver phenotype. Unexpectedly, our study found that whole-body Marc1 deficiency in mouse is not protective against hepatic triglyceride accumulation, liver inflammation or fibrosis. In attempts to explain the lack of the observed phenotype, we discovered that Marc1 plays only a minor role in mouse liver while its paralogue Marc2 is the main Marc family enzyme in mice. Our findings highlight the major difference in MARC1 physiological function between human and mouse.

2024-02-22 | GSE255944 | GEO

Oxyl and hydroxyl radical transfer in mitochondrial amidoxime reducing component-catalyzed nitrite reduction.

Project description:A combination of electron paramagnetic resonance (EPR) spectroscopy and computational approaches has provided insight into the nature of the reaction coordinate for the one-electron reduction of nitrite by the mitochondrial amidoxime reducing component (mARC) enzyme. The results show that a paramagnetic Mo(V) species is generated when reduced enzyme is exposed to nitrite, and an analysis of the resulting EPR hyperfine parameters confirms that mARC is remarkably similar to the low-pH form of sulfite oxidase. Two mechanisms for nitrite reduction have been considered. The first shows a modest reaction barrier of 14 kcal/mol for the formation of ·NO from unprotonated nitrite substrate. In marked contrast, protonation of the substrate oxygen proximal to Mo in the Mo(IV)-O-N-O substrate-bound species results in barrierless conversion to products. A fragment orbital analysis reveals a high degree of Mo-O(H)-N-O covalency that provides a π-orbital pathway for one-electron transfer to the substrate and defines orbital constraints on the Mo-substrate geometry for productive catalysis in mARC and other pyranopterin molybdenum enzymes that catalyze this one-electron transformation.

| S-EPMC4872596 | biostudies-literature

The mitochondrial amidoxime-reducing component (mARC1) is a novel signal-anchored protein of the outer mitochondrial membrane.

Project description:The mitochondrial amidoxime-reducing component (mARC) was recently discovered as the fifth eukaryotic molybdenum cofactor-containing enzyme. The human genome encodes two mARC proteins, mARC1 and mARC2, sharing significant homologies with respect to sequence and function. Whereas mARC2 was identified as a mitochondrial enzyme, the subcellular localization of mARC1 has remained uncharacterized, although the similarity of both proteins suggested identical subcellular localizations. In addition, neither mARC1 nor mARC2 could be attributed unambiguously to one of the four mitochondrial subcompartments. Accordingly, mechanisms triggering the subcellular distribution of both enzymes have been unexplored so far. Here, we shed light on the subcellular localization of mARC1 and demonstrate that it is integrated into the outer mitochondrial membrane. The C-terminal catalytic domain of the protein remains exposed to the cytosol and confers an N((in))-C((out)) membrane orientation of mARC1. This localization is triggered by the N terminus of the enzyme, being composed of a weak N-terminal mitochondrial targeting signal and a downstream transmembrane helix. We demonstrate the transmembrane domain of mARC1 to be sufficient for mitochondrial targeting and the N-terminal targeting signal to function as a supportive receptor for the outer mitochondrial membrane. According to its localization and targeting mechanism, we classify mARC1 as a novel signal-anchored mitochondrial protein. During mitochondrial import, mARC1 is not processed, and membrane integration proceeds membrane potential independently but requires external ATP, which finally results in the assembly of mARC1 into high oligomeric protein complexes.

| S-EPMC3525010 | biostudies-literature

Mitochondrial amidoxime-reducing component 2 (MARC2) has a significant role in N-reductive activity and energy metabolism.

Project description:The mitochondrial amidoxime-reducing component (MARC) is a mammalian molybdenum-containing enzyme. All annotated mammalian genomes harbor two MARC genes, MARC1 and MARC2, which share a high degree of sequence similarity. Both molybdoenzymes reduce a variety of N-hydroxylated compounds. Besides their role in N-reductive drug metabolism, only little is known about their physiological functions. In this study, we characterized an existing KO mouse model lacking the functional MARC2 gene and fed a high-fat diet and also performed in vivo and in vitro experiments to characterize reductase activity toward known MARC substrates. MARC2 KO significantly decreased reductase activity toward several N-oxygenated substrates, and for typical MARC substrates, only small residual reductive activity was still detectable in MARC2 KO mice. The residual detected reductase activity in MARC2 KO mice could be explained by MARC1 expression that was hardly unaffected by KO, and we found no evidence of significant activity of other reductase enzymes. These results clearly indicate that MARC2 is mainly responsible for N-reductive biotransformation in mice. Striking phenotypical features of MARC2 KO mice were lower body weight, increased body temperature, decreased levels of total cholesterol, and increased glucose levels, supporting previous findings that MARC2 affects energy pathways. Of note, the MARC2 KO mice were resistant to high-fat diet-induced obesity. We propose that the MARC2 KO mouse model could be a powerful tool for predicting MARC-mediated drug metabolism and further investigating MARC's roles in energy homeostasis.

| S-EPMC6873197 | biostudies-literature

Structural studies of the molybdenum center of mitochondrial amidoxime reducing component (mARC) by pulsed EPR spectroscopy and 17O-labeling.

Project description:Mitochondrial amidoxime reducing components (mARC-1 and mARC-2) represent a novel group of Mo-containing enzymes in eukaryotes. These proteins form the catalytic part of a three-component enzyme complex known to be responsible for the reductive activation of several N-hydroxylated prodrugs. No X-ray crystal structures are available for these enzymes as yet. A previous biochemical investigation [Wahl, B., et al. (2010) J. Biol. Chem., 285, 37847-37859 ] has revealed that two of the Mo coordination positions are occupied by sulfur atoms from a pyranopterindithiolate (molybdopterin, MPT) cofactor. In this work, we have used continuous wave and pulsed electron paramagnetic resonance (EPR) spectroscopy and density functional theoretical (DFT) calculations to determine the nature of remaining ligands in the Mo(V) state of the active site of mARC-2. Experiments with samples in D(2)O have identified the exchangeable equatorial ligand as a hydroxyl group. Experiments on samples in H(2)(17)O-enriched buffer have shown the presence of a slowly exchangeable axial oxo ligand. Comparison of the experimental (1)H and (17)O hyperfine interactions with those calculated using DFT has shown that the remaining nonexchangeable equatorial ligand is, most likely, protein-derived and that the possibility of an equatorial oxo ligand can be excluded.

| S-EPMC3222081 | biostudies-literature

Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17-beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms.

Project description:Genome-wide association studies in adults have identified variants in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) and mitochondrial amidoxime reducing component 1 (MTARC1) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in patatin-like phospholipase domain-containing protein 3 (PNPLA3). Genotype-histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T>TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7; 95% confidence interval, 0.6-0.9) and a lower grade of portal inflammation (p < 0.001). rs2642438G>A in MTARC1 was associated with a lower grade of hepatic steatosis (p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective -TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down-regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1. Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.

| S-EPMC9315139 | biostudies-literature

A novel mitochondrial amidoxime reducing component 2 is a favorable indicator of cancer and suppresses the progression of hepatocellular carcinoma by regulating the expression of p27.

Project description:Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality in the United States. Exploring the mechanism of HCC and identifying ideal targets is critical. In the present study, we demonstrated metabolism dysfunction might be a key diver for the development of HCC. The mitochondrial amidoxime reducing component 2 (MARC2) as a newly discovered molybdenum enzyme was downregulated in human HCC tissues and HCC cells. Downregulated MARC2 was significantly associated with clinicopathological characteristics of HCC, such as tumor size, AFP levels, and tumor grade and was an independent risk factor of poor prognosis. Both in vitro and in vivo studies suggested that MARC2 suppressed the progression of HCC by regulating the protein expression level of p27. The Hippo signaling pathway and RNF123 were required for this process. Moreover, MARC2 regulated expression of HNF4A via the Hippo signaling pathway. HNF4A was recruited to the promoter of MARC2 forming a feedback loop. MARC2 levels were downregulated by methylation. We demonstrated the prognostic value of MARC2 in HCC and determined the mechanism by which MARC2 suppressed the progression of HCC in this study. These findings may lead to new therapeutic targets for HCC.

| S-EPMC7498369 | biostudies-literature

Missense variant in TREML2 protects against Alzheimer's disease.

Project description:TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.

| S-EPMC3961557 | biostudies-literature

The N-reductive system composed of mitochondrial amidoxime reducing component (mARC), cytochrome b5 (CYB5B) and cytochrome b5 reductase (CYB5R) is regulated by fasting and high fat diet in mice.

Project description:The mitochondrial amidoxime reducing component mARC is the fourth mammalian molybdenum enzyme. The protein is capable of reducing N-oxygenated structures, but requires cytochrome b5 and cytochrome b5 reductase for electron transfer to catalyze such reactions. It is well accepted that the enzyme is involved in N-reductive drug metabolism such as the activation of amidoxime prodrugs. However, the endogenous function of the protein is not fully understood. Among other functions, an involvement in lipogenesis is discussed. To study the potential involvement of the protein in energy metabolism, we tested whether the mARC protein and its partners are regulated due to fasting and high fat diet in mice. We used qRT-PCR for expression studies, Western Blot analysis to study protein levels and an N-reductive biotransformation assay to gain activity data. Indeed all proteins of the N-reductive system are regulated by fasting and its activity decreases. To study the potential impact of these changes on prodrug activation in vivo, another mice experiment was conducted. Model compound benzamidoxime was injected to mice that underwent fasting and the resulting metabolite of the N-reductive reaction, benzamidine, was determined. Albeit altered in vitro activity, no changes in the metabolite concentration in vivo were detectable and we can dispel concerns that fasting alters prodrug activation in animal models. With respect to high fat diet, changes in the mARC proteins occur that result in increased N-reductive activity. With this study we provide further evidence that the endogenous function of the mARC protein is linked with lipid metabolism.

| S-EPMC4140751 | biostudies-literature

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