Abstract
Recently two novel enzymes were identified in the outer mitochondrial membrane, mARC1 and mARC2. These molybdenum containing enzymes can reduce a variety of N-hydroxylated compounds, such as N-hydroxy-guanidines and sulfohydroxamic acids, as well as convert nitrite into nitric oxide (NO). However, their endogenous functions remain unknown. Here we demonstrate a specific developmental pattern of expression of these enzymes. mARC1, but not mARC2, was found to be expressed in fetal human liver, whereas both, in particular mARC2, are abundant in adult liver and also expressed in omental and subcutaneous fat. Caloric diet restriction of obese patients caused a decreased expression of mARC2 in liver, similar to that seen in the livers of starved rats. Knock down of mARC2 expression by siRNA in murine adipocytes had statistically significant effect on the level of diglycerides and on the fatty acid composition of some triglycerides, concomitantly a clear trend toward the reduced formation of most of triglyceride and phospholipid species was observed. The involvement of mARC2 in the metabolism of the hepatotoxic drug ximelagatran was evaluated in hepatocytes and adipocytes. Ximelagatran was shown to cause oxidative stress and knock down of mARC2 in adipocytes prevented ximelagatran induced inhibition of mitochondrial respiration. In conclusion, our data indicate that mARC1 and mARC2 have different developmental expression profiles, and that mARC2 is involved in lipogenesis, is regulated by nutritional status and responsible for activation of ximelagatran into a mitotoxic metabolite(s).
Highlights
A novel mitochondrial amidoxime reductase enzyme system has been identified in mammals and subsequently the individual components have been characterized
In order to examine the developmental pattern of the expression of mARC1 and mARC2, the mRNA levels of both genes were analyzed in 88 adult and 14 fetal human livers (S1 Fig, Fig 1A)
MARC2 is only expressed in the adult livers, only very low levels are observed in the fetal tissues, suggesting that the expression of mARC2 is developmentally regulated while the expression of mARC1 is not
Summary
A novel mitochondrial amidoxime reductase enzyme system has been identified in mammals and subsequently the individual components have been characterized. Human mARC liver, kidney and adipose tissues where the highest specific activity was found to be associated with the outer mitochondrial membrane fractions [1,2,3]. This enzyme complex was shown to be composed of the electron transport proteins, such as mitochondrial cytochrome b5 type B (CYB5B) and NADH cytochrome b5 reductase (CYB5R) and a third component called the mitochondrial reducing component 1 and 2 (mARC1 and mARC2) [1, 2]. Human mARC1 and mARC2 are localized in the close proximity on chromosome 1 (location 1q41) only 58 kb apart of each other and at present not much is known about their gene regulation and tissue expression
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