Increased mitochondrial electron transport chain activity at complex I is regulated by N-acetylcysteine in lymphocytes of patients with systemic lupus erythematosus.

Abstract

AIMS:

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.

INNOVATION:

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: Edward Doherty, Zachary Oaks, Andras Perl
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 21 Issue 1 Pg. 56-65 (Jul 01 2014) ISSN: 1557-7716 [Electronic] United States
• PMID: 24673154 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hydrogen Peroxide
• Electron Transport Complex I
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Adult
• Aged
• Cells, Cultured
• Electron Transport Complex I (metabolism)
• Female
• Humans
• Hydrogen Peroxide (metabolism)
• Lupus Erythematosus, Systemic (metabolism)
• Lymphocytes (drug effects, metabolism)
• Middle Aged
• Oxygen Consumption (drug effects, physiology)
• Young Adult