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

TL;DR

ATPIF1 knockout in mice causes anemia by impairing red blood cell development in the bone marrow, but the spleen compensates by boosting erythroid production.

Contribution

This study reveals ATPIF1's role in erythroid development and the spleen's compensatory function in mitochondrial dysfunction-induced anemia.

Findings

ATPIF1 deficiency impairs bone marrow erythroid development and mitochondrial function.

The spleen compensates with extramedullary erythropoiesis, reducing apoptosis and increasing heme-related gene activity.

Heme levels decrease in the bone marrow but remain stable in the spleen.

Abstract

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.

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