{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T01:31:20Z","timestamp":1791509480098,"version":"4.3.4"},"reference-count":49,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2016,10,27]],"date-time":"2016-10-27T00:00:00Z","timestamp":1477526400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH (National Institute of Allergy and Infectious Diseases and National Institute of Diabetes and Digestive and Kidney Diseases)","award":["DK-078922"],"award-info":[{"award-number":["DK-078922"]}]},{"name":"NIH (National Institute of Allergy and Infectious Diseases and National Institute of Diabetes and Digestive and Kidney Diseases)","award":["AI-072648"],"award-info":[{"award-number":["AI-072648"]}]},{"DOI":"10.13039\/100001026","name":"Central New York Community Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001026","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mitochondria were isolated from lupus\u2010prone MRL\/lpr, C57BL\/6.lpr, and MRL mice, age\u2010matched autoimmunity\u2010resistant C57BL\/6 mice as negative controls, and transaldolase\u2010deficient 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\u2013\u03b2<jats:sub>2<\/jats:sub>\u2010glycoprotein I (anti\u2010\u03b2<jats:sub>2<\/jats:sub>GPI) autoantibodies were measured by enzyme\u2010linked immunosorbent assay in mice treated with rapamycin or mice treated with a solvent control.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mitochondrial oxygen consumption was increased in the livers of 4\u2010week\u2010old, disease\u2010free MRL\/lpr mice relative to age\u2010matched controls. Levels of the mitophagy initiator dynamin\u2010related 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\u2010\u03b2<jats:sub>2<\/jats:sub>GPI were elevated preceding the development of nephritis in 4\u2010week\u2010old MRL, C57BL\/6.lpr, and MRL\/lpr mice. Transaldolase\u2010deficient mice showed increased oxygen consumption, depletion of Drp1, activation of mTORC1, and elevated expression of NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3), a pro\u2010oxidant subunit of ETC complex I, as well as increased production of aCL and anti\u2010\u03b2<jats:sub>2<\/jats:sub>GPI autoantibodies. Treatment with rapamycin selectively blocked mTORC1 activation, NDUFS3 expression, and aPL production both in transaldolase\u2010deficient mice and in lupus\u2010prone mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In lupus\u2010prone mice, mTORC1\u2010dependent mitochondrial dysfunction contributes to the generation of aPL, suggesting that such mechanisms may represent a treatment target in patients with SLE.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39791","type":"journal-article","created":{"date-parts":[[2016,6,22]],"date-time":"2016-06-22T19:12:48Z","timestamp":1466622768000},"page":"2728-2739","source":"Crossref","is-referenced-by-count":128,"title":["Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus\u2010Prone Mice"],"prefix":"10.1002","volume":"68","author":[{"given":"Zachary","family":"Oaks","sequence":"first","affiliation":[{"name":"State University of New 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