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ORIGINAL RESEARCH article

Front. Cell Dev. Biol.

Sec. Cell Growth and Division

Volume 13 - 2025 | doi: 10.3389/fcell.2025.1675547

Splenic compensation alleviates impaired-development of bone marrow terminal erythroid to attenuate anemia in ATPIF1 knockout mice

Provisionally accepted
Jing  FengJing Feng1Yue  ZhaoYue Zhao1Meiqi  XuMeiqi Xu1Mengjia  LiMengjia Li2Shuchou  XiaShuchou Xia1Jianping  YeJianping Ye1,3,4*
  • 1Institute of Trauma and Metabolism, Zhengzhou Central Hospital, Zhengzhou, China
  • 2Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  • 3Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
  • 4Zhengzhou Key laboratory of Obesity Research, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China

The final, formatted version of the article will be published soon.

ATPIF1 (ATPase Inhibitory Factor 1) is a critical regulatory factor of mitochondrial ATP synthase, maintaining ATP homeostasis by modulating ATP synthesis and hydrolysis. In this study, we investigated the consequences of ATPIF1 knockout (KO) on terminal erythroid development and mitochondrial metabolic adaptation in mice. ATPIF1-KO mice exhibited significant reductions in peripheral red blood cell (RBC) counts, hemoglobin, and hematocrit. Mechanistic studies identified impaired development of bone marrow (BM) erythroid, accompanied by robust compensatory erythroid development in the spleen. Integrated RNA-seq and metabolomic analyses revealed that ATPIF1 deficiency disrupted cell proliferation and mitochondrial function in oxidative phosphorylation (OXPHOS) and the tricarboxylic acid (TCA) cycle of BM erythroblasts, leading to defective terminal differentiation of erythrocytes. BM-derived erythroid cells showed a reduction in proliferation, mitochondrial mass, and reactive oxygen species (ROS) levels with an increase in apoptosis. Conversely, the spleen displayed extramedullary erythroid development characterized by enhanced proliferation, reduced apoptosis, increased reductive stress, and upregulation of heme-related genes. Heme levels were decreased in the bone marrow, but not in the spleen. These findings establish ATPIF1 as a key regulator of terminal erythroid development and highlight the essential compensatory role of the spleen in maintaining erythropoietic homeostasis under KO-induced mitochondrial dysfunction. Our work provides new insight into the pathophysiology of mitochondrial-related anemias and potential therapeutic targets.

Keywords: ATPIF1, Mitochondria, Erythroid development, proliferation, Heme

Received: 29 Jul 2025; Accepted: 30 Sep 2025.

Copyright: © 2025 Feng, Zhao, Xu, Li, Xia and Ye. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Jianping Ye, yejianping@zzu.edu.cn

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