MAVS Aggregates Impair Cardiolipin Function and Mitochondrial Fission in SLE

线粒体功能障碍，特征为线粒体跨膜蛋白持续升高， 潜在的，缺乏线粒体分裂，氧化应激和减少能源生产发挥了根本作用， SLE患者T细胞活化异常中的作用。线粒体分裂不仅需要创造新的 线粒体，而且还在高水平细胞应激期间去除受损的线粒体。为什么在T细胞中 SLE患者线粒体分裂受到抑制，线粒体积聚并促进细胞死亡尚不清楚。 在健康条件下，分裂由动力蛋白相关蛋白1（Drp 1）诱导， 细胞质转化为线粒体。最新研究表明，Drp1激活和募集到线粒体是 由心磷脂（CL）介导，心磷脂是一种独特存在于线粒体内膜和外膜中的脂质。虽然 抗CL和相关磷脂的自身抗体是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。也不知道CL与Drp1的相互作用是否被抑制， SLE和哪些细胞因子可以抑制这种相互作用。 我们的初步数据表明，单独的氧化应激可以诱导MAVS的寡聚化， 在病毒感染期间通常被激活的抗病毒信号蛋白。我们发现SLE的淋巴细胞 患者有自发性低聚MAVS，这可能与CL有关， 寡聚MAVS不经历Drp1依赖性分裂，也不参与线粒体自噬。 因此，我们假设MAVS寡聚体阻断CL与Drp1的结合，从而阻碍分离 正常和功能失调的线粒体。我们提出MitoQ和线粒体靶向肽， 与CL结合将恢复裂变和线粒体自噬。我们的工作将首次确定 SLE患者中I型IFN信号和抗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.