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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

Received: 　　Accepted:

Corresponding author: 刘静　　E-mail:

DOI: 10.13294/j.aps.2025.0053

Citing This Article：

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).