title: Increased mitochondrial electron transport chain activity at complex I is regulated by N-acetylcysteine in lymphocytes of patients with systemic lupus erythematosus.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1 Division of Rheumatology, Department of Medicine, College of Medicine, State University of New York , Upstate Medical University, Syracuse, New York.
authors.forename: Edward
authors.initials: E
authors.lastname: Doherty
authors.forename: Zachary
authors.initials: Z
authors.lastname: Oaks
authors.forename: Andras
authors.initials: A
authors.lastname: Perl
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000378:metabolism*; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: D006861:Hydrogen Peroxide; D042967:Electron Transport Complex I; D000111:Acetylcysteine