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.

新的证据支持线粒体功能障碍导致系统性红斑狼疮 (SLE) 发病机制。在这里，我们发现，程序性线粒体去除（哺乳动物红细胞生成的标志）在系统性红斑狼疮中存在缺陷。具体来说，我们证明在人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），该系统先于线粒体的自噬去除，并且是自噬去除线粒体所必需的。该途径的缺陷会导致 SLE 患者携带线粒体（Mito ⁺ RBC）的红细胞（RBC）积聚，并与疾病活动相关。抗体介导的 Mito ⁺ RBC 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，同时携带 Mito ⁺ RBC 和调理抗体的 SLE 患者显示出最高水平的血液 IFN 刺激基因 (ISG) 特征，这是 SLE 的一个显着特征。