AIF loss deregulates hematopoiesis and reveals different adaptive metabolic responses in bone marrow cells and thymocytes
AIF loss deregulates hematopoiesis and reveals different adaptive metabolic responses in bone marrow cells and thymocytes
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DOI：
10.1038/s41418-017-0035-x
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发表时间：
2018-05-01
影响因子：
12.4
通讯作者：
Susin, Santos A.
中科院分区：
文献类型：
--
作者：
Cabon, Lauriane;Bertaux, Audrey;Susin, Santos A.
线粒体代谢是一个严格调控的过程，在造血细胞的整个生命周期中发挥着核心作用。在此，我们分析了线粒体氧化磷酸化（OXPHOS）/代谢紊乱与造血诱导因子（AIF）的细胞特异性造血消融相关的后果。AIF-null（AIF（-/Y））小鼠发生全血细胞减少症，与骨髓（BM）细胞减少和胸腺萎缩相关。虽然骨髓细胞相对较少，但B细胞和红细胞谱系发生改变，前体B细胞、前成红细胞I和嗜碱性成红细胞II的频率增加。在双阴性（DN）未成熟状态下，T细胞群体随着胸腺生成阻断而显著减少，伴随DN 1积累和延迟的DN 2/DN 3和DN 3/DN 4转换。在BM细胞中，由AIF损失引起的OXPHOS/代谢功能障碍通过线粒体生物合成的增强和向无氧糖酵解的转变来平衡。然而，在半胱天冬酶非依赖性过程中，产生的过量活性氧损害了造血干细胞（HSC）和祖细胞的活力。这导致HSC池的逐渐耗尽，在甲基纤维素测定中BM祖细胞分化成集落的能力降低，以及缺乏细胞自主HSC体内再增殖潜力。与BM细胞相反，AIF（-/Y）胸腺细胞通过增强脂肪酸β-氧化来补偿OXPHOS分解。通过过表达CPT 1、ACADL和PDK 4，促进脂肪酸β-氧化的三种关键酶（例如，棕榈酸同化），AIF（-/Y）胸腺细胞恢复AIF（+/Y）细胞的ATP水平。因此，通过给动物喂食补充抗氧化剂的高脂肪饮食，可以在体内显著重建AIF（-/）Y胸腺生成。总的来说，我们的数据表明，由AIF调节的线粒体信号对造血决策至关重要。作为线粒体代谢和造血细胞命运之间的联系，AIF介导的OXPHOS调节代表了开发新的免疫调节疗法的靶点。
Mitochondrial metabolism is a tightly regulated process that plays a central role throughout the lifespan of hematopoietic cells. Herein, we analyze the consequences of the mitochondrial oxidative phosphorylation (OXPHOS)/metabolism disorder associated with the cell-specific hematopoietic ablation of apoptosis-inducing factor (AIF). AIF-null (AIF(-/Y)) mice developed pancytopenia that was associated with hypocellular bone marrow (BM) and thymus atrophy. Although myeloid cells were relatively spared, the B-cell and erythroid lineages were altered with increased frequencies of precursor B cells, pro-erythroblasts I, and basophilic erythroblasts II. T-cell populations were dramatically reduced with a thymopoiesis blockade at a double negative (DN) immature state, with DN1 accumulation and delayed DN2/DN3 and DN3/DN4 transitions. In BM cells, the OXPHOS/metabolism dysfunction provoked by the loss of AIF was counterbalanced by the augmentation of the mitochondrial biogenesis and a shift towards anaerobic glycolysis. Nevertheless, in a caspase-independent process, the resulting excess of reactive oxygen species compromised the viability of the hematopoietic stem cells (HSC) and progenitors. This led to the progressive exhaustion of the HSC pool, a reduced capacity of the BM progenitors to differentiate into colonies in methylcellulose assays, and the absence of cell-autonomous HSC repopulating potential in vivo. In contrast to BM cells, AIF(-/Y) thymocytes compensated for the OXPHOS breakdown by enhancing fatty acid beta-oxidation. By over-expressing CPT1, ACADL and PDK4, three key enzymes facilitating fatty acid beta-oxidation (e.g., palmitic acid assimilation), the AIF(-/Y) thymocytes retrieved the ATP levels of the AIF(+/Y) cells. As a consequence, it was possible to significantly reestablish AIF(-/)Y thymopoiesis in vivo by feeding the animals with a high-fat diet complemented with an antioxidant. Overall, our data reveal that the mitochondrial signals regulated by AIF are critical to hematopoietic decision-making. Emerging as a link between mitochondrial metabolism and hematopoietic cell fate, AIFmediated OXPHOS regulation represents a target for the development of new immunomodulatory therapeutics.