1 Division of Rheumatology, Department of Medicine, College of Medicine, State University of New York , Upstate Medical University, Syracuse, New York.
Antioxid Redox Signal. 2014 Jul 1;21(1):56-65. doi: 10.1089/ars.2013.5702. Epub 2014 Apr 23.
Systemic lupus erythematosus (SLE) patients' peripheral blood lymphocytes (PBL) show mitochondrial dysfunction and oxidative stress. To determine the electrochemical bases of mitochondrial dysfunction, we measured electron transport chain (ETC) activity and its regulation by N-acetylcysteine (NAC) that reversed glutathione depletion and improved disease activity in SLE. ETC activity was assessed in PBL of 69 SLE patients and 37 healthy donors. Negatively isolated T cells were examined in 7 SLE patients, 11 healthy donors, and 10 nonlupus inflammatory arthritis (IA) donors.
O₂ consumption (in nmol/ml/min) by lupus PBL was increased at baseline (SLE: 2.492±0.196, control: 2.137±0.153; p=0.027) and with complex IV substrates (SLE: 7.722±0.419, control: 7.006±0.505; p=0.028). SLE PBL consumed more O₂ upon in-chamber T-cell activation (p=0.012). After overnight T-cell stimulation, ETC activity of SLE PBL was 2.27-fold increased through complex I (SLE: 1.606±0.273, control: 0.709±0.169; p=0.001) and, to a lesser extent, through complex IV. Likewise, complex I activity was elevated in negatively isolated "untouched" T cells of SLE patients (1.816±0.180) relative to healthy controls (0.917±0.094; p=0.0003) and IA disease controls studied in parallel (1.057±0.199; p=0.0308). NAC diminished O₂ consumption through complex I and H₂O₂ levels both in SLE and in control PBL.
O₂ consumption was found to be increased in SLE patients' PBL relative to control subjects evaluated in parallel. ETC complex I is identified as the main source of oxidative stress in SLE.
Lupus PBL exhibit increased O₂ consumption through mitochondrial ETC complex I that is inhibited by NAC, which may have therapeutic efficacy through reducing oxidative stress in SLE.
系统性红斑狼疮（SLE）患者外周血淋巴细胞（PBL）存在线粒体功能障碍和氧化应激。为了确定线粒体功能障碍的电化学基础，我们测量了电子传递链（ETC）的活性，以及 N-乙酰半胱氨酸（NAC）对其的调节作用，NAC 可以逆转谷胱甘肽耗竭并改善 SLE 患者的疾病活动度。ETC 活性在 69 名 SLE 患者和 37 名健康供体的 PBL 中进行了评估。在 7 名 SLE 患者、11 名健康供体和 10 名非狼疮性炎症性关节炎（IA）供体的阴性分离 T 细胞中进行了检查。
狼疮 PBL 的 O₂消耗（nmol/ml/min）在基线时增加（SLE：2.492±0.196，对照：2.137±0.153；p=0.027），并且在使用 IV 复合物底物时增加（SLE：7.722±0.419，对照：7.006±0.505；p=0.028）。SLE PBL 在室内 T 细胞激活时消耗更多的 O₂（p=0.012）。经过一夜的 T 细胞刺激后，SLE PBL 的 ETC 活性通过复合物 I 增加了 2.27 倍（SLE：1.606±0.273，对照：0.709±0.169；p=0.001），并且在一定程度上通过复合物 IV 增加。同样，与健康对照组（0.917±0.094；p=0.0003）和并行研究的 IA 疾病对照组（1.057±0.199；p=0.0308）相比，SLE 患者阴性分离的“未触及”T 细胞中的复合物 I 活性也升高。（1.816±0.180）。NAC 可降低 SLE 和对照 PBL 中通过复合物 I 的 O₂消耗和 H₂O₂水平。
与并行评估的对照组相比，我们发现 SLE 患者的 PBL 中 O₂消耗增加。ETC 复合物 I 被鉴定为 SLE 中氧化应激的主要来源。
狼疮 PBL 通过线粒体 ETC 复合物 I 表现出增加的 O₂消耗，NAC 可抑制该复合物 I，这可能通过减少 SLE 中的氧化应激而具有治疗功效。
