The mitochondrial iron transporter ABCB7 is required for B cell development, proliferation, and class switch recombination in mice

Lehrke, Michael Jonathan; Shapiro, Michael J.; Rajcula, Matthew; Kennedy, Madeleine M; McCue, Shaylene; Medina, Kay L.; Shapiro, Virginia Smith

doi:10.7554/elife.69621

Cited by 12 publications

(14 citation statements)

References 98 publications

(172 reference statements)

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“…Tfrc is the cellular iron gate, controlling the uptake of circulating transferrin‐bound iron to cells (Fillebeen et al, 2019). Abcb7 is involved in the transfer of iron from mitochondria to the cytoplasm and the maturation of cytoplasmic iron sulfur (Fe/S) proteins (Lehrke et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

Cross‐species comparison illuminates the importance of iron homeostasis for splenic anti‐immunosenescence

He,

et al. 2023

Aging Cell

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Although immunosenescence may result in increased morbidity and mortality, many mammals have evolved effective immune coping strategies to extend their lifespans. Thus, the immune systems of long‐lived mammals present unique models to study healthy longevity. To identify the molecular clues of anti‐immunosenescence, we first built high‐quality reference genome for a long‐lived myotis bat, and then compared three long‐lived mammals (i.e., bat, naked mole rat, and human) versus the short‐lived mammal, mouse, in splenic immune cells at single‐cell resolution. A close relationship between B:T cell ratio and immunosenescence was detected, as B:T cell ratio was much higher in mouse than long‐lived mammals and significantly increased during aging. Importantly, we identified several iron‐related genes that could resist immunosenescence changes, especially the iron chaperon, PCBP1, which was upregulated in long‐lived mammals but dramatically downregulated during aging in all splenic immune cell types. Supportively, immune cells of mouse spleens contained more free iron than those of bat spleens, suggesting higher level of ROS‐induced damage in mouse. PCBP1 downregulation during aging was also detected in hepatic but not pulmonary immune cells, which is consistent with the crucial roles of spleen and liver in organismal iron recycling. Furthermore, PCBP1 perturbation in immune cell lines would result in cellular iron dyshomeostasis and senescence. Finally, we identified two transcription factors that could regulate PCBP1 during aging. Together, our findings highlight the importance of iron homeostasis in splenic anti‐immunosenescence, and provide unique insight for improving human healthspan.

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Section: Resultsmentioning

confidence: 99%

Cross‐species comparison illuminates the importance of iron homeostasis for splenic anti‐immunosenescence

He,

et al. 2023

Aging Cell

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“…Mitoferrin 1/2 are critical enzymes for transporting iron from cytosol into mitochondria. In contrast, ABCB7/8 are responsible for delivering iron from mitochondria to cytosol [ 21 , 53 , 54 ]. It is interestingly noted that, although IRP1 , IRP2 , ferritin , FPN , ABCB7 , and ABCB8 were all upregulated by rotenone, only ABCB8 could be reversed by H 2 S cotreatment.…”

Section: Discussionmentioning

confidence: 99%

H2S Protects from Rotenone-Induced Ferroptosis by Stabilizing Fe-S Clusters in Rat Cardiac Cells

Linjacki,

Wang,

Baath

et al. 2024

Cells

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Hydrogen sulfide (H2S) has been recently recognized as an important gasotransmitter with cardioprotections, and iron is vital for various cellular activities. This study explored the regulatory role of H2S on iron metabolism and mitochondrial functions in cultured rat cardiac cells. Rotenone, a mitochondrial complex I inhibitor, was used for establishing an in vitro model of ischemic cell damage. It was first found that rotenone induced oxidative stress and lipid peroxidation and decreased mitochondrial membrane potential and ATP generation, eventually causing cell death. The supplement of H2S at a physiologically relevant concentration protected from rotenone-induced ferroptotic cell death by reducing oxidative stress and mitochondrial damage, maintaining GPx4 expression and intracellular iron level. Deferiprone, an iron chelator, would also protect from rotenone-induced ferroptosis. Further studies demonstrated that H2S inhibited ABCB8-mediated iron efflux from mitochondria to cytosol and promoted NFS1-mediated Fe-S cluster biogenesis. It is also found that rotenone stimulated iron-dependent H2S generation. These results indicate that H2S would protect cardiac cells from ischemic damage through preserving mitochondrial functions and intracellular Fe-S cluster homeostasis.

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“…However, numerous ABC transporters are now recognized for filling essential functions within the adaptive immune system generally, and immunometabolism specifically. The obligate mitochondrial transporters ABCB7 and ABCB10, for example, are considered heme transporters based on their roles in erythropoiesis, and are necessary for the development of B cells and CD4 memory T cells, respectively (23,24). In addition, lipid and multi-drug transporters have recently emerged as key regulators of T cell metabolism and function (Table 1).…”

Section: Abc Transporters In T Cellsmentioning

confidence: 99%

ATP-dependent transporters: emerging players at the crossroads of immunity and metabolism

Balasubramanian,

Sundrud

2023

Front. Immunol.

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Nearly 50 ATP-binding cassette (ABC) transporters are encoded by mammalian genomes. These transporters are characterized by conserved nucleotide-binding and hydrolysis (i.e., ATPase) domains, and power directional transport of diverse substrate classes – ions, small molecule metabolites, xenobiotics, hydrophobic drugs, and even polypeptides – into or out of cells or subcellular organelles. Although immunological functions of ABC transporters are only beginning to be unraveled, emerging literature suggests these proteins have under-appreciated roles in the development and function of T lymphocytes, including many of the key effector, memory and regulatory subsets that arise during responses to infection, inflammation or cancers. One transporter in particular, MDR1 (Multidrug resistance-1; encoded by the ABCB1 locus in humans), has taken center stage as a novel player in immune regulation. Although MDR1 remains widely viewed as a simple drug efflux pump in tumor cells, recent evidence suggests that this transporter fills key endogenous roles in enforcing metabolic fitness of activated CD4 and CD8 T cells. Here, we summarize current understanding of the physiological functions of ABC transporters in immune regulation, with a focus on the anti-oxidant functions of MDR1 that may shape both the magnitude and repertoires of antigen-specific effector and memory T cell compartments. While much remains to be learned about the functions of ABC transporters in immunobiology, it is already clear that they represent fertile new ground, both for the definition of novel immunometabolic pathways, and for the discovery of new drug targets that could be leveraged to optimize immune responses to vaccines and cancer immunotherapies.

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The mitochondrial iron transporter ABCB7 is required for B cell development, proliferation, and class switch recombination in mice

Cited by 12 publications

References 98 publications

Cross‐species comparison illuminates the importance of iron homeostasis for splenic anti‐immunosenescence

Cross‐species comparison illuminates the importance of iron homeostasis for splenic anti‐immunosenescence

H2S Protects from Rotenone-Induced Ferroptosis by Stabilizing Fe-S Clusters in Rat Cardiac Cells

ATP-dependent transporters: emerging players at the crossroads of immunity and metabolism

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