Caza Tiffany N, Fernandez David R, Talaber Gergely, Oaks Zachary, Haas Mark, Madaio Michael P, Lai Zhi-Wei, Miklossy Gabriella, Singh Ram R, Chudakov Dmitriy M, Malorni Walter, Middleton Frank, Banki Katalin, Perl Andras
Departments of Medicine, Microbiology, and Immunology, Biochemistry and Molecular Biology, Neuroscience and Physiology, and Pathology, SUNY Upstate Medical University, Syracuse, New York, USA.
Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Ann Rheum Dis. 2014 Oct;73(10):1888-97. doi: 10.1136/annrheumdis-2013-203794. Epub 2013 Jul 29.
Accumulation of mitochondria underlies T-cell dysfunction in systemic lupus erythematosus (SLE). Mitochondrial turnover involves endosomal traffic regulated by HRES-1/Rab4, a small GTPase that is overexpressed in lupus T cells. Therefore, we investigated whether (1) HRES-1/Rab4 impacts mitochondrial homeostasis and (2) Rab geranylgeranyl transferase inhibitor 3-PEHPC blocks mitochondrial accumulation in T cells, autoimmunity and disease development in lupus-prone mice.
Mitochondria were evaluated in peripheral blood lymphocytes (PBL) of 38 SLE patients and 21 healthy controls and mouse models by flow cytometry, microscopy and western blot. MRL/lpr mice were treated with 125 μg/kg 3-PEHPC or 1 mg/kg rapamycin for 10 weeks, from 4 weeks of age. Disease was monitored by antinuclear antibody (ANA) production, proteinuria, and renal histology.
Overexpression of HRES-1/Rab4 increased the mitochondrial mass of PBL (1.4-fold; p=0.019) and Jurkat cells (2-fold; p=0.000016) and depleted the mitophagy initiator protein Drp1 both in human (-49%; p=0.01) and mouse lymphocytes (-41%; p=0.03). Drp1 protein levels were profoundly diminished in PBL of SLE patients (-86±3%; p=0.012). T cells of 4-week-old MRL/lpr mice exhibited 4.7-fold over-expression of Rab4A (p=0.0002), the murine homologue of HRES-1/Rab4, and depletion of Drp1 that preceded the accumulation of mitochondria, ANA production and nephritis. 3-PEHPC increased Drp1 (p=0.03) and reduced mitochondrial mass in T cells (p=0.02) and diminished ANA production (p=0.021), proteinuria (p=0.00004), and nephritis scores of lupus-prone mice (p<0.001).
These data reveal a pathogenic role for HRES-1/Rab4-mediated Drp1 depletion and identify endocytic control of mitophagy as a treatment target in SLE.
线粒体堆积是系统性红斑狼疮（SLE）中T细胞功能障碍的基础。线粒体周转涉及由HRES-1/Rab4调节的内体运输，HRES-1/Rab4是一种小GTP酶，在狼疮T细胞中过度表达。因此，我们研究了（1）HRES-1/Rab4是否影响线粒体稳态，以及（2）Rab香叶基香叶基转移酶抑制剂3-PEHPC是否能阻止T细胞中的线粒体堆积、自身免疫以及狼疮易感小鼠的疾病发展。
通过流式细胞术、显微镜检查和蛋白质印迹法，对38例SLE患者和21例健康对照者的外周血淋巴细胞（PBL）以及小鼠模型中的线粒体进行评估。从4周龄开始，给MRL/lpr小鼠用125μg/kg 3-PEHPC或1mg/kg雷帕霉素治疗10周。通过抗核抗体（ANA）产生、蛋白尿和肾脏组织学监测疾病情况。
HRES-1/Rab4的过度表达增加了PBL（1.4倍；p=0.019）和Jurkat细胞（2倍；p=0.000016）的线粒体质量，并使人类（-49%；p=0.01）和小鼠淋巴细胞（-41%；p=0.03）中的线粒体自噬起始蛋白Drp1减少。SLE患者PBL中的Drp1蛋白水平显著降低（-86±3%；p=0.012）。4周龄MRL/lpr小鼠的T细胞中Rab4A（HRES-1/Rab4的小鼠同源物）过度表达4.7倍（p=0.0002），并且在出现线粒体堆积、ANA产生和肾炎之前，Drp1就已减少。3-PEHPC增加了Drp1（p=0.03），减少了T细胞中的线粒体质量（p=0.02），并减少了ANA产生（p=0.021）、蛋白尿（p=0.00004）以及狼疮易感小鼠的肾炎评分（p<0.001）。
这些数据揭示了HRES-1/Rab4介导的Drp1减少的致病作用，并确定线粒体自噬的内吞控制作为SLE的一个治疗靶点。
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