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抑制线粒体代谢酶OGDC影响红系发育

胡彬^1,2, 李茂华^1,2, 龚晗^1,2, 韩璐^1,2, 刘静^1,2,*

¹中南大学生命科学学院，长沙 410013；²中南大学血液学基础与应用湖南省重点实验室，长沙 410078

摘要

线粒体代谢为细胞提供能量与血红素前体物质，在红系发育中扮演着至关重要的角色。作为线粒体三羧酸(tricarboxylic acid, TCA)循环中的核心限速酶，酮戊二酸脱氢酶复合体(oxoglutarate dehydrogenase complex, OGDC)水平在红系分化过程中逐渐升高，提示其在红系发育中具有重要作用。本研究旨在探讨OGDC在红系发育中的作用及其机制。用OGDC的竞争性抑制剂CPI-613处理红系前体细胞，结果显示，CPI-613抑制促红细胞生成素(erythropoietin, EPO)诱导的人CD34+造血干细胞向红系分化和脱核，抑制细胞增殖，诱导凋亡。体内实验结果显示，CPI-613可抑制小鼠急性溶血性贫血的恢复。进一步的机制研究结果显示，CPI-613诱导红系前体细胞中活性氧(reactive oxygen species, ROS)增加，抑制线粒体呼吸并导致其损伤，抑制血红素合成，从而抑制红系分化。临床研究结果显示，真性红细胞增多症(polycythemia vera, PV)患者骨髓细胞中酮戊二酸脱氢酶(oxoglutarate dehydrogenase, OGDH)蛋白表达水平上调，CPI-613显著抑制PV患者红系前体细胞的过度增殖和分化。以上结果表明，OGDC在正常红系发育中发挥关键作用，抑制其活性是治疗PV的潜在新策略。

关键词： 红系发育; 酮戊二酸脱氢酶复合体(OGDC); CPI-613; 线粒体代谢; 真性红细胞增多症

Inhibition of the mitochondrial metabolic enzyme OGDC affects erythroid development

HU Bin^1,2, LI Mao-Hua^1,2, GONG Han^1,2, HAN Lu^1,2, LIU Jing^1,2,*

¹School of Life Sciences, Central South University, Changsha 410013, China；²Key Laboratory of Basic and Applied Hematology in Hunan Province, Central South University, Changsha 410078, China

Abstract

Mitochondrial metabolism is crucial for providing energy and heme precursors during erythroid development. Oxoglutarate dehydrogenase complex (OGDC) is a key enzyme in the mitochondrial tricarboxylic acid (TCA) cycle, and its level gradually increases during erythroid development, indicating its significant role in erythroid development. The aim of the present study was to explore the role and mechanism of OGDC in erythroid development. In this study, we treated erythroid progenitor cells with CPI-613, a novel lipoic acid analog that competitively inhibits OGDC. The results showed that CPI-613 inhibited erythropoietin (EPO)-induced differentiation and enucleation of human CD34+ hematopoietic stem cells into erythroid cells, suppressed cell proliferation, and induced apoptosis. The results of in vivo experiments showed that CPI-613 also hindered the recovery of mice from acute hemolytic anemia. Further mechanism research results showed that CPI-613 increased reactive oxygen species (ROS) in erythroid progenitor cells, inhibited mitochondrial respiration, caused mitochondrial damage, and suppressed heme synthesis, thereby inhibiting erythroid differentiation. Clinical research results showed that oxoglutarate dehydrogenase (OGDH) protein expression levels were upregulated in bone marrow cells of polycythemia vera (PV) patients. Treatment with CPI-613 significantly inhibited the excessive proliferation and differentiation of erythroid progenitor cells of the PV patients. These findings demonstrates the critical role of OGDC in normal erythroid development, suggesting that inhibiting its activity could be a novel therapeutic strategy for treating PV.

Key words: erythroid development; oxoglutarate dehydrogenase complex (OGDC); CPI-613; mitochondrial metabolism; polycythemia vera

收稿日期：　　录用日期：

通讯作者：刘静　　E-mail:

DOI: 10.13294/j.aps.2025.0053

引用本文：

胡彬, 李茂华, 龚晗, 韩璐, 刘静. 抑制线粒体代谢酶OGDC影响红系发育[J]. 生理学报 2025; 77 (3): 395-407.

HU Bin, LI Mao-Hua, GONG Han, HAN Lu, LIU Jing. Inhibition of the mitochondrial metabolic enzyme OGDC affects erythroid development. Acta Physiol Sin 2025; 77 (3): 395-407 (in Chinese with English abstract).