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Abstract：
Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito+ RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito+ RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito+ RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.
摘要：
新的证据支持线粒体功能障碍有助于系统性红斑狼疮（SLE）的发病机制。在这里，我们展示了程序化的线粒体去除，哺乳动物红细胞生成的标志,是有缺陷的SLE。具体来说,我们证明在人类红系细胞成熟过程中，缺氧诱导因子（HIF）介导的代谢开关负责激活泛素-蛋白酶体系统（UPS），这在线粒体的自噬去除之前是必要的。该途径的缺陷导致SLE患者中携带线粒体（MitoRBC）的红细胞（RBC）积累，并与疾病活动相关。Mito+RBC的抗体介导的内化通过激活巨噬细胞中的cGAS诱导I型干扰素(IFN)的产生。因此，SLE患者携带米托+红细胞和调理抗体显示最高水平的血液干扰素刺激基因（ISG）的特征，SLE的一个显著特征。
