MAVS Aggregates Impair Cardiolipin Function and Mitochondrial Fission in SLE

线粒体功能障碍，特征是线粒体跨膜持续升高 潜在的，缺乏线粒体分裂，氧化应激和能量产生减少起着根本的作用 系统性红斑狼疮患者T细胞异常活化的作用线粒体的分裂不仅需要创造新的 不仅是为了在高水平的细胞应激状态下移除受损的线粒体，也是为了保护线粒体。为什么在T细胞中 系统性红斑狼疮患者线粒体分裂受到抑制，线粒体积累并促进细胞死亡尚不清楚。 在健康条件下，动力蛋白相关蛋白1(Drp1)转位到 细胞质到线粒体。最新研究表明，DRp1对线粒体的激活和募集是 由心磷脂(CL)介导，这是一种唯一存在于线粒体内膜和外膜的脂类。虽然 抗CL自身抗体和相关磷脂是SLE的已知生物标志物，CL在SLE中的作用 细胞在过去从未被研究过。目前也不清楚CL与Drp1的相互作用是否受到抑制 以及哪些细胞因素可以抑制这种相互作用。 我们的初步数据表明，氧化应激本身就可以诱导线粒体MAV的寡聚化 通常在病毒感染期间被激活的抗病毒信号蛋白。我们发现SLE患者的淋巴细胞 患者自发地寡聚MAV，这可以与CL和线粒体与CL相关 寡聚化的MAV不经历依赖于DRp1的分裂，也不参与有丝分裂。 因此，我们假设MAVS寡聚体封闭了CL与DRP1的结合，从而阻碍了分离 正常和功能失调的线粒体。我们认为MitoQ和线粒体靶向多肽，这些多肽 与CL结合将恢复分裂和有丝分裂。我们的工作将首次建立起 系统性红斑狼疮患者的I型干扰素签名和抗CL自身抗体的存在。

Mitochondrial dysfunction, characterized by the persistent elevation of the mitochondrial transmembrane potential, lack of mitochondrial fission, oxidative stress and decreased energy production plays a fundamental role in abnormal T-cell activation in patients with SLE. Mitochondrial fission is not only needed to create new mitochondria, but also to remove damaged mitochondria during high levels of cellular stress. Why in T cells of SLE patients mitochondrial fission is inhibited and mitochondria accumulate and promote cell death is not known. Under healthy conditions fission is induced by dynamin-related protein 1 (Drp1) upon translocation from cytoplasm to mitochondria. Latest studies suggest that Drp1 activation and recruitment to mitochondria is mediated by Cardiolipin (CL), a lipid uniquely found in mitochondrial inner and outer membranes. Although autoantibodies against CL and related phospholipids are known biomarkers of SLE, the function of CL in SLE cells has never been investigated in the past. Neither is it known whether CL interaction with Drp1 is inhibited in SLE and what cellular factors could inhibit this interaction. Our preliminary data shows that oxidative stress alone can induce oligomerization of MAVS, a mitochondrial antiviral signaling protein that is normally activated during viral infections. We show that lymphocytes from SLE patients have spontaneously oligomerized MAVS, which can associate with CL and that mitochondria with oligomerized MAVS do not undergo Drp1-dependent fission and do not engage in mitophagy. We thus hypothesize that MAVS oligomers occlude CL from binding to Drp1 and therefore hinder the segregation of normal and dysfunctional mitochondria. We propose that MitoQ and mitochondria targeted peptides, which bind to CL will restore fission and mitophagy. Our work will establish for the first time the missing link between type I IFN signature and the presence of anti-CL autoantibodies in SLE patients.