Glyoxylate reductase: Definitive identification in human liver mitochondria, its importance for the compartment-specific detoxification of glyoxylate

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Sander F. Garrelfs, Serhii Chornyi, Heleen te Brinke, Jos Ruiter, Jaap Groothoff, Ronald J. A. Wanders
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Abstract

Glyoxylate is a key metabolite generated from various precursor substrates in different subcellular compartments including mitochondria, peroxisomes, and the cytosol. The fact that glyoxylate is a good substrate for the ubiquitously expressed enzyme lactate dehydrogenase (LDH) requires the presence of efficient glyoxylate detoxification systems to avoid the formation of oxalate. Furthermore, this detoxification needs to be compartment-specific since LDH is actively present in multiple subcellular compartments including peroxisomes, mitochondria, and the cytosol. Whereas the identity of these protection systems has been established for both peroxisomes and the cytosol as concluded from the deficiency of alanine glyoxylate aminotransferase (AGT) in primary hyperoxaluria type 1 (PH1) and glyoxylate reductase (GR) in PH2, the glyoxylate protection system in mitochondria has remained less well defined. In this manuscript, we show that the enzyme glyoxylate reductase has a bimodal distribution in human embryonic kidney (HEK293), hepatocellular carcinoma (HepG2), and cervical carcinoma (HeLa) cells and more importantly, in human liver, and is actively present in both the mitochondrial and cytosolic compartments. We conclude that the metabolism of glyoxylate in humans requires the complicated interaction between different subcellular compartments within the cell and discuss the implications for the different primary hyperoxalurias.

Abstract Image

乙醛酸还原酶:在人类肝脏线粒体中的明确鉴定及其对特定区室乙醛酸解毒的重要性。
乙醛酸盐是由线粒体、过氧物酶体和细胞质等不同亚细胞区室中的各种前体底物生成的一种关键代谢物。乙醛酸是普遍表达的乳酸脱氢酶(LDH)的良好底物,这就要求存在高效的乙醛酸解毒系统,以避免形成草酸盐。此外,由于 LDH 活跃于过氧物酶体、线粒体和细胞质等多个亚细胞区室,因此这种解毒系统需要具有区室特异性。虽然从原发性高草酸尿症 1 型(PH1)中丙氨酸乙醛酸氨基转移酶(AGT)的缺乏和 PH2 中乙醛酸还原酶(GR)的缺乏中可以得出结论,这些保护系统在过氧物酶体和细胞质中的身份已经确定,但线粒体中的乙醛酸保护系统仍然没有得到很好的界定。在这篇手稿中,我们发现乙醛酸还原酶在人类胚胎肾(HEK293)、肝癌(HepG2)和宫颈癌(HeLa)细胞中呈双峰分布,更重要的是,它在人类肝脏中也呈双峰分布,并活跃地存在于线粒体和细胞质中。我们的结论是,乙醛酸盐在人体内的代谢需要细胞内不同亚细胞区室之间复杂的相互作用,并讨论了对不同原发性高氧尿症的影响。
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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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