Thies Bastian, Meyer-Schwesinger Catherine, Lamp Jessica, Schweizer Michaela, Koeller David M, Ullrich Kurt, Braulke Thomas, Mühlhausen Chris
Department of Biochemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Biochim Biophys Acta. 2013 Oct;1832(10):1463-72. doi: 10.1016/j.bbadis.2013.04.019. Epub 2013 Apr 24.
The metabolic disorder glutaric aciduria type 1 (GA1) is caused by deficiency of the mitochondrial glutaryl-CoA dehydrogenase (GCDH), leading to accumulation of the pathologic metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in blood, urine and tissues. Affected patients are prone to metabolic crises developing during catabolic conditions, with an irreversible destruction of striatal neurons and a subsequent dystonic-dyskinetic movement disorder. The pathogenetic mechanisms mediated by GA and 3OHGA have not been fully characterized. Recently, we have shown that GA and 3OHGA are translocated through membranes via sodium-dependent dicarboxylate cotransporter (NaC) 3, and organic anion transporters (OATs) 1 and 4. Here, we show that induced metabolic crises in Gcdh(-/-) mice lead to an altered renal expression pattern of NaC3 and OATs, and the subsequent intracellular GA and 3OHGA accumulation. Furthermore, OAT1 transporters are mislocalized to the apical membrane during metabolic crises accompanied by a pronounced thinning of proximal tubule brush border membranes. Moreover, mitochondrial swelling and increased excretion of low molecular weight proteins indicate functional tubulopathy. As the data clearly demonstrate renal proximal tubule alterations in this GA1 mouse model during induced metabolic crises, we propose careful evaluation of renal function in GA1 patients, particularly during acute crises. Further studies are needed to investigate if these findings can be confirmed in humans, especially in the long-term outcome of affected patients.
1型戊二酸血症（GA1）这种代谢紊乱疾病是由线粒体戊二酰辅酶A脱氢酶（GCDH）缺乏引起的，导致病理性代谢产物戊二酸（GA）和3-羟基戊二酸（3OHGA）在血液、尿液和组织中蓄积。受影响的患者在分解代谢状态下容易发生代谢危机，伴有纹状体神经元的不可逆破坏以及随后的张力障碍-运动障碍。GA和3OHGA介导的发病机制尚未完全明确。最近，我们发现GA和3OHGA通过钠依赖性二羧酸共转运蛋白（NaC）3以及有机阴离子转运蛋白（OAT）1和4转运穿过细胞膜。在此，我们表明在Gcdh（-/-）小鼠中诱发的代谢危机导致NaC3和OATs的肾表达模式改变，以及随后细胞内GA和3OHGA的蓄积。此外，在代谢危机期间，OAT1转运蛋白错误定位于顶端膜，同时近端小管刷状缘膜明显变薄。而且，线粒体肿胀和低分子量蛋白质排泄增加表明存在功能性肾小管病变。由于数据清楚地证明了在这种GA1小鼠模型中诱发代谢危机期间肾近端小管的改变，我们建议对GA1患者的肾功能进行仔细评估，尤其是在急性危机期间。需要进一步研究以调查这些发现是否能在人类中得到证实，特别是在受影响患者的长期预后方面。
