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Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus-Prone Mice.
- Source :
-
Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2016 Nov; Vol. 68 (11), pp. 2728-2739. - Publication Year :
- 2016
-
Abstract
- Objective: Antiphospholipid antibodies (aPL) constitute a diagnostic criterion of systemic lupus erythematosus (SLE), and aPL have been functionally linked to liver disease in patients with SLE. Since the mechanistic target of rapamycin (mTOR) is a regulator of oxidative stress, a pathophysiologic process that contributes to the development of aPL, this study was undertaken in a mouse model of SLE to examine the involvement of liver mitochondria in lupus pathogenesis.<br />Methods: Mitochondria were isolated from lupus-prone MRL/lpr, C57BL/6.lpr, and MRL mice, age-matched autoimmunity-resistant C57BL/6 mice as negative controls, and transaldolase-deficient mice, a strain that exhibits oxidative stress in the liver. Electron transport chain (ETC) activity was assessed using measurements of oxygen consumption. ETC proteins, which are regulators of mitochondrial homeostasis, and the mTOR complexes mTORC1 and mTORC2 were examined by Western blotting. Anticardiolipin (aCL) and anti-β <subscript>2</subscript> -glycoprotein I (anti-β <subscript>2</subscript> GPI) autoantibodies were measured by enzyme-linked immunosorbent assay in mice treated with rapamycin or mice treated with a solvent control.<br />Results: Mitochondrial oxygen consumption was increased in the livers of 4-week-old, disease-free MRL/lpr mice relative to age-matched controls. Levels of the mitophagy initiator dynamin-related protein 1 (Drp1) were depleted while the activity of mTORC1 was increased in MRL/lpr mice. In turn, mTORC2 activity was decreased in MRL and MRL/lpr mice. In addition, levels of aCL and anti-β <subscript>2</subscript> GPI were elevated preceding the development of nephritis in 4-week-old MRL, C57BL/6.lpr, and MRL/lpr mice. Transaldolase-deficient mice showed increased oxygen consumption, depletion of Drp1, activation of mTORC1, and elevated expression of NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3), a pro-oxidant subunit of ETC complex I, as well as increased production of aCL and anti-β <subscript>2</subscript> GPI autoantibodies. Treatment with rapamycin selectively blocked mTORC1 activation, NDUFS3 expression, and aPL production both in transaldolase-deficient mice and in lupus-prone mice.<br />Conclusion: In lupus-prone mice, mTORC1-dependent mitochondrial dysfunction contributes to the generation of aPL, suggesting that such mechanisms may represent a treatment target in patients with SLE.<br /> (© 2016, The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)
- Subjects :
- Animals
Antibodies, Anticardiolipin biosynthesis
Antibodies, Anticardiolipin drug effects
Antibodies, Anticardiolipin immunology
Antibodies, Antiphospholipid drug effects
Antibodies, Antiphospholipid immunology
Antibody Formation drug effects
Antibody Formation immunology
Blotting, Western
Disease Models, Animal
Dynamins metabolism
Electron Transport Chain Complex Proteins drug effects
Enzyme-Linked Immunosorbent Assay
Female
Immunosuppressive Agents pharmacology
Lupus Erythematosus, Systemic chemically induced
Lupus Erythematosus, Systemic metabolism
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Mice
Mice, Inbred C57BL
Mice, Inbred MRL lpr
Mice, Knockout
Mitochondria, Liver drug effects
Oxidative Stress drug effects
Oxygen Consumption drug effects
Sirolimus pharmacology
Transaldolase genetics
beta 2-Glycoprotein I immunology
Antibodies, Antiphospholipid biosynthesis
Electron Transport Chain Complex Proteins metabolism
Lupus Erythematosus, Systemic immunology
Mitochondria, Liver metabolism
Multiprotein Complexes metabolism
Oxidative Stress immunology
Oxygen Consumption immunology
TOR Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2326-5205
- Volume :
- 68
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Arthritis & rheumatology (Hoboken, N.J.)
- Publication Type :
- Academic Journal
- Accession number :
- 27332042
- Full Text :
- https://doi.org/10.1002/art.39791