Mitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis

Abstract

Adenine nucleotide translocases (ANTs) transport ADP and ATP through mitochondrial inner membrane, thus playing an essential role for energy metabolism of eukaryotic cells. Mice have three ANT paralogs, Ant1 (Slc25a4), Ant2 (Slc25a5) and Ant4 (Slc25a31), which are expressed in a tissue-dependent manner. While knockout mice have been characterized with Ant1 and Ant4 genes, which resulted in exercise intolerance and male infertility, respectively, the role of the ubiquitously expressed Ant2 gene in animal development has not been fully demonstrated. Here, we generated Ant2 hypomorphic mice by targeted disruption of the gene, in which Ant2 expression is largely depleted. The mice showed apparently normal embryonic development except pale phenotype along with a reduced birth rate. However, postnatal growth was severely retarded with macrocytic anemia, B lymphocytopenia, lactic acidosis and bloated stomach, and died within 4 weeks. Ant2 depletion caused anemia in a cell-autonomous manner by maturation arrest of erythroid precursors with increased reactive oxygen species and premature deaths. B-lymphocyte development was similarly affected by Ant2 depletion, and splenocytes showed a reduction in maximal respiration capacity and cellular ATP levels as well as an increase in cell death accompanying mitochondrial permeability transition pore opening. In contrast, myeloid, megakaryocyte and T-lymphocyte lineages remained apparently intact. Erythroid and B-cell development may be particularly vulnerable to Ant2 depletion-mediated mitochondrial dysfunction and oxidative stress.

H+ transport is an integral function of the mitochondrial ADP/ATP carrier

“…2c ). I H was not significantly altered in heart or kidney of AAC2 hypomorphic mice 42 ( Extended Data Fig. 6a and b ), and was CATR-sensitive likely due to compensation with AAC1 42 ( Extended Data Fig.…”

“…In mice, AAC1 and AAC2 are the only somatic isoforms 3 , 4 . AAC1 expression is highest in heart and SM, and AAC2 – in kidney 4 , 42 . In heart of AAC1 −/− mice 5 , 43 , AA failed to induce I H at negative potentials in all mitoplasts tested except one ( Fig.…”

iTRAQ-Based Quantitative Proteomics Identifies Potential Regulatory Proteins Involved in Chicken Eggshell Brownness

“…The SLC25A5 protein is an inner membrane transporter that facilitates the exchange of ATP and ADP and also contributes to heme biosynthesis by serving as an alternative protoporphyrin IX transport pathway to import it into the mitochondrial matrix for heme synthesis [59, 60]. SLC25A5 gene knockout mice showed a pale phenotype and postnatal growth was severely retarded with macrocytic anemia because of maturation arrest of the erythrocyte precursor [61]. Therefore, the up-regulated SLC25A5 protein expression in the light group would cause more protoporphyrin IX to be imported into mitochondrial matrix for heme synthesis.…”

ANT2-defective fibroblasts exhibit normal mitochondrial bioenergetics

“…Recently, the Ant2 −/− mouse was characterized with severe postnatal growth retardation, macrocytic anemia, B lymphocytopenia, lactic acidosis, bloated stomach, and death within 4 weeks. Interestingly, unlike ANT2-defective fibroblasts, Ant2 −/− mouse splenocytes exhibited decreased mitochondrial respiration as well as decreased mitochondrial potential and decreased relative intracellular ATP levels [4] .…”

“…Based on the role of ANT2 in maintaining mitochondrial membrane potential in cancer cells [1] , [2] , we hypothesized that cells lacking ANT2 would, as recently reported in Ant2 knockout mouse [4] , exhibit a respiratory chain deficiency, decreased mitochondrial membrane potential and low intracellular ATP levels. We also hypothesized that the absence of ANT2 would increase their sensitivity to mitochondrial oxidative phosphorylation (OXPHOS) inhibitors, because with mitochondrial ATP synthesis being inhibited, cells would rely on the transport of cytosolic ATP into the mitochondrial matrix (ANT2) to maintain mitochondrial homeostasis and eventually survive.…”