Hu Bin, Li Mao-Hua, Gong Han, Han Lu, Liu Jing
School of Life Sciences, Central South University, Changsha 410013, China.
Key Laboratory of Basic and Applied Hematology in Hunan Province, Central South University, Changsha 410078, China.
Sheng Li Xue Bao. 2025 Jun 25;77(3):395-407. doi: 10.13294/j.aps.2025.0053.
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 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 up-regulated 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.
线粒体代谢对于在红细胞生成过程中提供能量和血红素前体至关重要。氧代戊二酸脱氢酶复合体（OGDC）是线粒体三羧酸（TCA）循环中的关键酶，其水平在红细胞生成过程中逐渐升高，表明其在红细胞生成中具有重要作用。本研究的目的是探讨OGDC在红细胞生成中的作用及机制。在本研究中，我们用CPI-613处理红细胞祖细胞，CPI-613是一种新型硫辛酸类似物，可竞争性抑制OGDC。结果表明，CPI-613抑制促红细胞生成素（EPO）诱导的人CD34造血干细胞向红细胞的分化和去核，抑制细胞增殖，并诱导细胞凋亡。实验结果表明，CPI-613还阻碍了小鼠从急性溶血性贫血中恢复。进一步的机制研究结果表明，CPI-613增加了红细胞祖细胞中的活性氧（ROS），抑制线粒体呼吸，导致线粒体损伤，并抑制血红素合成，从而抑制红细胞分化。临床研究结果表明，真性红细胞增多症（PV）患者骨髓细胞中氧代戊二酸脱氢酶（OGDH）蛋白表达水平上调。用CPI-613治疗可显著抑制PV患者红细胞祖细胞的过度增殖和分化。这些发现证明了OGDC在正常红细胞生成中的关键作用，表明抑制其活性可能是治疗PV的一种新的治疗策略。
