{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T04:08:41Z","timestamp":1792814921528,"version":"4.5.0"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3389\/fcell.2025.1675547","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T05:31:16Z","timestamp":1760679076000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Splenic compensation alleviates impaired-development of bone marrow terminal erythroid to attenuate anemia in ATPIF1 knockout mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Jing","family":"Feng","sequence":"first","affiliation":[{"name":"Institute of Trauma and Metabolism, Zhengzhou Central Hospital Affiliated to Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Trauma and Metabolism, Zhengzhou Central Hospital Affiliated to Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiqi","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Trauma and Metabolism, Zhengzhou Central Hospital Affiliated to Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hematology, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuchou","family":"Xia","sequence":"additional","affiliation":[{"name":"Institute of Trauma and Metabolism, Zhengzhou Central Hospital Affiliated to Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Ye","sequence":"additional","affiliation":[{"name":"Institute of Trauma and Metabolism, Zhengzhou Central Hospital Affiliated to Zhengzhou University","place":["Zhengzhou, China"]},{"name":"Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University","place":["Zhengzhou, China"]},{"name":"Zhengzhou Key laboratory of Obesity Research, Zhengzhou Central Hospital Affiliated to Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1126\/science.aax7063","article-title":"A cytosine deaminase for programmable single-base RNA editing","volume":"365","author":"Abudayyeh","year":"2019","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e111699","DOI":"10.15252\/embj.2022111699","article-title":"Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies","volume":"42","author":"Acin-Perez","year":"2023","journal-title":"Embo J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1038\/ng.2007.62","article-title":"Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism","volume":"40","author":"Aragones","year":"2008","journal-title":"Nat. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"glad142","DOI":"10.1093\/gerona\/glad142","article-title":"Plasma level of ATPase inhibitory factor 1 and intrinsic capacity in community-dwelling older adults: prospective data from the MAPT study","volume":"79","author":"da Silva","year":"2024","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1146\/annurev-nutr-062320-112625","article-title":"Molecular mechanisms of iron and heme metabolism","volume":"42","author":"Dutt","year":"2022","journal-title":"Annu. Rev. Nutr."},{"key":"B6","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.trecan.2023.10.002","article-title":"Reductive stress in cancer: coming out of the shadows","volume":"10","author":"Ge","year":"2024","journal-title":"Trends Cancer"},{"key":"B7","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1089\/ars.2021.0137","article-title":"The multifaceted ATPase inhibitory factor 1 (IF1) in energy metabolism reprogramming and mitochondrial dysfunction: a new player in age-associated disorders?","volume":"37","author":"Gore","year":"2022","journal-title":"Antioxid. Redox Signal"},{"key":"B8","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.tcb.2011.04.003","article-title":"Formation of mammalian erythrocytes: chromatin condensation and enucleation","volume":"21","author":"Ji","year":"2011","journal-title":"Trends Cell Biol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1016\/j.cmet.2021.08.008","article-title":"Erythrocyte-derived mitochondria take to the lupus stage","volume":"33","author":"Lepelley","year":"2021","journal-title":"Cell Metab."},{"key":"B10","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1097\/MOH.0b013e32834521f3","article-title":"Membrane assembly during erythropoiesis","volume":"18","author":"Liu","year":"2011","journal-title":"Curr. Opin. Hematol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e43","DOI":"10.1182\/blood-2012-09-456079","article-title":"Quantitative analysis of murine terminal erythroid differentiation in vivo: novel method to study normal and disordered erythropoiesis","volume":"121","author":"Liu","year":"2013","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1038\/ncb3527","article-title":"Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation","volume":"19","author":"Liu","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1111\/bjh.19600","article-title":"Mitochondrial regulation of erythropoiesis in homeostasis and disease","volume":"205","author":"Menon","year":"2024","journal-title":"Br. J. Haematol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1038\/s41556-023-01280-z","article-title":"NAD(+) regulates nucleotide metabolism and genomic DNA replication","volume":"25","author":"Munk","year":"2023","journal-title":"Nat. Cell Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e00067","DOI":"10.1042\/bsr20130078","article-title":"IF1, a natural inhibitor of mitochondrial ATP synthase, is not essential for the normal growth and breeding of mice","volume":"33","author":"Nakamura","year":"2013","journal-title":"Biosci. Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1097\/moh.0000000000000234","article-title":"Metabolic regulation of hematopoietic stem cell commitment and erythroid differentiation","volume":"23","author":"Oburoglu","year":"2016","journal-title":"Curr. Opin. Hematol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1038\/s42255-020-0250-5","article-title":"Dihydroxyacetone phosphate signals glucose availability to mTORC1","volume":"2","author":"Orozco","year":"2020","journal-title":"Nat. Metab."},{"key":"B18","doi-asserted-by":"publisher","first-page":"3","DOI":"10.3389\/fphys.2014.00003","article-title":"Primitive and definitive erythropoiesis in mammals","volume":"5","author":"Palis","year":"2014","journal-title":"Front. Physiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1182\/blood.v89.1.1","article-title":"Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells","volume":"89","author":"Ponka","year":"1997","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e0221472","DOI":"10.1371\/journal.pone.0221472","article-title":"Erythroid differentiation displays a peak of energy consumption concomitant with glycolytic metabolism rearrangements","volume":"14","author":"Richard","year":"2019","journal-title":"PLoS One"},{"key":"B21","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.ccr.2004.11.022","article-title":"Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase","volume":"7","author":"Selak","year":"2005","journal-title":"Cancer Cell"},{"key":"B22","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1038\/nature11536","article-title":"Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts","volume":"491","author":"Shah","year":"2012","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e136055","DOI":"10.1172\/jci136055","article-title":"Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity","volume":"131","author":"Sharma","year":"2021","journal-title":"J. Clin. Invest"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1089\/ars.2019.7803","article-title":"Metabolic responses to reductive stress","volume":"32","author":"Xiao","year":"2020","journal-title":"Antioxid. Redox Signal"},{"key":"B25","doi-asserted-by":"publisher","first-page":"895521","DOI":"10.3389\/fcell.2022.895521","article-title":"Regulation of heme synthesis by mitochondrial homeostasis proteins","volume":"10","author":"Yien","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2114740","DOI":"10.1080\/2162402x.2022.2114740","article-title":"scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity","volume":"11","author":"Zhong","year":"2022","journal-title":"Oncoimmunology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"166820","DOI":"10.1016\/j.bbadis.2023.166820","article-title":"Enhanced glycolysis by ATPIF1 gene inactivation increased the anti-bacterial activities of neutrophils through induction of ROS and lactic acid","volume":"1869","author":"Zhong","year":"2023","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2025.1675547\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T13:45:02Z","timestamp":1770299102000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2025.1675547\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,17]]},"references-count":27,"alternative-id":["10.3389\/fcell.2025.1675547"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2025.1675547","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,17]]},"article-number":"1675547"}}