Background: Citrin (mitochondrial aspartate–glutamate transporter) deficiency causes the failures in both carbohydrate-energy metabolism and the urea cycle, and the alterations in the serum levels of several amino acids in the stages of newborn (NICCD) and adult (CTLN2). However, the clinical manifestations are resolved between the NICCD and CTLN2, but the reasons are still unclear. This study evaluated the serum amino acid profile in citrin-deficient children during the healthy stage.
Methods: Using HPLC-MS/MS analysis, serum amino acids were evaluated among 20 citrin-deficient children aged 5–13 years exhibiting normal liver function and 35 age-matched healthy controls.
Results: The alterations in serum amino acids characterized in the NICCD and CTLN2 stages were not observed in the citrin-deficient children. Amino acids involved in the urea cycle, including arginine, ornithine, citrulline, and aspartate, were comparable in the citrin-deficient children to the respective control levels, but serum urea was twofold higher, suggestive of a functional urea cycle. The blood sugar level was normal, but glucogenic amino acids and glutamine were significantly decreased in the citrin-deficient children compared to those in the controls. In addition, significant increases of ketogenic amino acids, branched-chain amino acids (BCAAs), a valine intermediate 3-hydroxyisobutyrate, and β-alanine were also found in the citrin-deficient children.
Conclusion: The profile of serum amino acids in the citrin-deficient children during the healthy stage showed different characteristics from the NICCD and CTLN2 stages, suggesting that the failures in both urea cycle function and energy metabolism might be compensated by amino acid metabolism.
Synopsis: In the citrin-deficient children during the healthy stage, the characteristics of serum amino acids, including decrease of glucogenic amino acids, and increase of ketogenic amino acids, BCAAs, valine intermediate, and β-alanine, were found by comparison to the age-matched healthy control children, and it suggested that the characteristic alteration of serum amino acids may be resulted from compensation for energy metabolism and ammonia detoxification.
Age-matched control study Amino acids Energy metabolism Gluconeogenesis Mitochondria transporter Urea cycle
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Details of the contributions of individual authors as (a) conception and design, (b) data analysis, (c) data interpretation, (d) drafting the article, (e) revising the article, and (f) clinical diagnosis/treatment and sample collection: Miyazaki T: (a, b, c, d); Nagasaka H: (a, b, c, d, f); Komatsu H: (c, f); Inui A: (c, f); Morioka I: (c, f); Tsukahara H: (c, f); SKaji S: (c, f); Hirayama S: (c, f); Miida T: (c, f); Kondou H: (c, f); Ihara K: (c, f); Yagi M: (c, f); Kizaki Z: (c, f); Bessho K: (c, f); Kodama T: (c, f); Iijima K: (c, f); Yorifuji T: (c, f); Matsuzaki Y: (e); and Honda A: (a, b, c, e).
Avogaro A, Bier DM (1989) Contribution of 3-hydroxyisobutyrate to the measurement of 3-hydroxybutyrate in human plasma: comparison of enzymatic and gas-liquid chromatography-mass spectrometry assays in normal and in diabetic subjects. J Lipid Res 30:1811–1817PubMedGoogle Scholar
Chanprasert S, Scaglia F (2015) Adult liver disorders caused by inborn errors of metabolism: review and update. Mol Genet Metab 114:1–10CrossRefGoogle Scholar
Cooper AJ, Shurubor YI, Dorai T et al (2016) Omega-Amidase: an underappreciated, but important enzyme in L-glutamine and L-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases. Amino Acids 48:1–20CrossRefGoogle Scholar
Dang CV (2010) Glutaminolysis: supplying carbon or nitrogen or both for cancer cells? Cell Cycle 9:3884–3886CrossRefGoogle Scholar
Kobayashi K, Saheki T, Song YZ (1993–2017) Citrin deficiency. In: Pagon RA, Adam MP, Ardinger HH et al (eds) Citrin deficiency. University of Washington, Seattle, WAGoogle Scholar
Kobayashi K, Sinasac DS, Iijima M et al (1999) The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet 22:159–163CrossRefGoogle Scholar
Kobayashi K, Iijima M, Yasuda T et al (2000) Type II citrullinemia (citrin deficiency): a mysterious disease caused by a defect of calcium-binding mitochondrial carrier protein. Kluwer, Dordrecht, The NetherlandsGoogle Scholar
Komatsu M, Yazaki M, Tanaka N et al (2008) Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease. J Hepatol 49:810–820CrossRefGoogle Scholar
Komatsu M, Kimura T, Yazaki M et al (2015) Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARalpha. Biochim Biophys Acta 1852:473–481CrossRefGoogle Scholar
Marcadier JL, Smith AM, Pohl D et al (2013) Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria. Orphanet J Rare Dis 8:98CrossRefGoogle Scholar
Matsuzaki Y (2008) Total bile acids. Ishiyaku Publishers, Inc., TokyoGoogle Scholar
Miyazaki T, Honda A, Ikegami T et al (2015) Simultaneous quantification of salivary 3-hydroxybutyrate, 3-hydroxyisobutyrate, 3-hydroxy-3-methylbutyrate, and 2-hydroxybutyrate as possible markers of amino acid and fatty acid catabolic pathways by LC-ESI-MS/MS. Springerplus 4:494CrossRefGoogle Scholar
Nagasaka H, Komatsu H, Inui A et al (2017) Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment. Mol Genet Metab 120:207–212CrossRefGoogle Scholar
Palmieri L, Pardo B, Lasorsa FM et al (2001) Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. EMBO J 20:5060–5069CrossRefGoogle Scholar
Palmieri EM, Spera I, Menga A et al (2015) Acetylation of human mitochondrial citrate carrier modulates mitochondrial citrate/malate exchange activity to sustain NADPH production during macrophage activation. Biochim Biophys Acta 1847:729–738CrossRefGoogle Scholar
Pollitt RJ, Green A, Smith R (1985) Excessive excretion of beta-alanine and of 3-hydroxypropionic, R- and S-3-aminoisobutyric, R- and S-3-hydroxyisobutyric and S-2-(hydroxymethyl)butyric acids probably due to a defect in the metabolism of the corresponding malonic semialdehydes. J Inherit Metab Dis 8:75–79CrossRefGoogle Scholar
Reitzer LJ, Wice BM, Kennell D (1979) Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem 254:2669–2676PubMedGoogle Scholar
Saheki T, Kobayashi K (2002) Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet 47:333–341CrossRefGoogle Scholar
Saheki T, Song YZ (1993) Citrin deficiency. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews®, University of Washington, Seattle, WAGoogle Scholar
Saheki T, Kobayashi K, Miura T et al (1986) Serum amino acid pattern of type II citrullinemic patients and effect of oral administration of citrulline. J Clin Biochem Nutr 1:129–142CrossRefGoogle Scholar
Saheki T, Kobayashi K, Terashi M et al (2008) Reduced carbohydrate intake in citrin-deficient subjects. J Inherit Metab Dis 31:386–394CrossRefGoogle Scholar
Saheki T, Inoue K, Ono H et al (2012) Effects of supplementation on food intake, body weight and hepatic metabolites in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse model of human citrin deficiency. Mol Genet Metab 107:322–329CrossRefGoogle Scholar
Shimbo K, Oonuki T, Yahashi A, Hirayama K, Miyano H (2009) Precolumn derivatization reagents for high-speed analysis of amines and amino acids in biological fluid using liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 23:1483–1492CrossRefGoogle Scholar
Shimomura Y, Honda T, Shiraki M et al (2006) Branched-chain amino acid catabolism in exercise and liver disease. J Nutr 136:250S–253SCrossRefGoogle Scholar
Shiota M, Hiramatsu M, Fujimoto Y et al (1994) The capacity of the malate-aspartate shuttle differs between periportal and perivenous hepatocytes from rats. Arch Biochem Biophys 308:349–356CrossRefGoogle Scholar
Sinasac DS, Moriyama M, Jalil MA et al (2004) Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia. Mol Cell Biol 24:527–536CrossRefGoogle Scholar
Tamamori A, Fujimoto A, Okano Y et al (2004) Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. Pediatr Res 56:608–614CrossRefGoogle Scholar
Yasuda T, Yamaguchi N, Kobayashi K et al (2000) Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia. Hum Genet 107:537–545CrossRefGoogle Scholar