Katsuta Nana, Nagai Mime, Saruwatari Kaishi, Nakamura Michio, Nagai Ryoji
Laboratory of Food and Regulation Biology, Graduate School of Bioscience, Tokai University, Toroku 9-1-1, Higashi-ku, Kumamoto 862-8652, Japan.
Laboratory of Food and Regulation Biology, Department of Food and Life Sciences, School of Agriculture, Tokai University, Toroku 9-1-1, Higashi-ku, Kumamoto 862-8652, Japan.
J Clin Biochem Nutr. 2023 Mar;72(2):147-156. doi: 10.3164/jcbn.22-101. Epub 2023 Mar 1.
Mitochondrial stress increases the production of fumarate, an intermediate of the Krebs cycle. Fumarate non-enzymatically reacts with the thiol group of cysteine, leading to the production of -(2-succinyl)cysteine. Here, we quantified the concentration of fumarate, the free form of -(2-succinyl)cysteine, and advanced glycation end-products, including -(carboxymethyl)lysine and -(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine, in the serum of chronic kidney disease patients, using liquid chromatography-tandem mass spectrometry and an enzymatic assay. In a cross-sectional study, we evaluated the difference in metabolite concentration between healthy individuals ( = 22) and kidney transplant patients ( = 93). Additionally, we evaluated the metabolite concentration of end-stage renal disease patients ( = 17) before and 1, 3, 6, and 12 months after transplantation, in a longitudinal study. While the -(2-succinyl)cysteine and AGEs levels were significantly increased in accordance with the rising chronic kidney disease severity, they were significantly decreased after transplantation. However, fumarate levels were only significantly different in end-stage renal disease patients. The -(2-succinyl)cysteine levels correlated with the pre-existing kidney function marker. This study demonstrates that mitochondrial metabolic disorders contribute to impaired kidney function, and that measuring blood -(2-succinyl)cysteine levels may be a minimally invasive way to evaluate the metabolic change in chronic kidney disease.
线粒体应激会增加延胡索酸（三羧酸循环的一种中间产物）的生成。延胡索酸会与半胱氨酸的巯基发生非酶反应，生成S-(2-琥珀酰)半胱氨酸。在此，我们使用液相色谱-串联质谱法和酶法测定，对慢性肾病患者血清中的延胡索酸、游离形式的S-(2-琥珀酰)半胱氨酸以及晚期糖基化终产物（包括N-(羧甲基)赖氨酸和N-(5-羟基-5-甲基-4-咪唑啉-2-基)-鸟氨酸）的浓度进行了定量分析。在一项横断面研究中，我们评估了健康个体（n = 22）和肾移植患者（n = 93）之间代谢物浓度的差异。此外，在一项纵向研究中，我们评估了终末期肾病患者（n = 17）在移植前以及移植后1、3、6和12个月时的代谢物浓度。虽然S-(2-琥珀酰)半胱氨酸和晚期糖基化终产物水平随着慢性肾病严重程度的增加而显著升高，但在移植后它们显著降低。然而，只有终末期肾病患者的延胡索酸水平存在显著差异。S-(2-琥珀酰)半胱氨酸水平与原有的肾功能标志物相关。这项研究表明，线粒体代谢紊乱会导致肾功能受损，并且检测血液中S-(2-琥珀酰)半胱氨酸水平可能是评估慢性肾病代谢变化的一种微创方法。
