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However, the detailed mechanisms connecting these two factors remain poorly understood. This study hypothesizes that low but chronic interferon-gamma (IFN-\u03b3) plays a critical role in these processes. To explore this, we utilized ARE-Del mice, a model characterized by sustained low-level IFN-\u03b3 expression and lupus nephritis (LN)-like symptoms. Age- and tissue-dependent gene expression analyses in ARE-Del mice revealed significant suppression of mitochondrial complex I components and activities, particularly in the kidneys. The genotype-dependent suppression of mitochondrial complex I indicates early disruption, which leads to macrophage dysfunction. Notably, remission restored gene expression of mitochondrial complex I and macrophage dysfunction in isolated renal macrophages from NZB\/W lupus-prone mice. These findings suggest that chronic low-level IFN-\u03b3 disrupts mitochondrial complex I activity in macrophages, highlighting its role in the early pathogenesis of autoimmune diseases like lupus nephritis. This provides new insights into the molecular interactions underlying autoimmune pathogenesis and suggests potential targets for therapeutic intervention.<\/jats:p>","DOI":"10.3390\/ijms26010063","type":"journal-article","created":{"date-parts":[[2024,12,25]],"date-time":"2024-12-25T19:29:52Z","timestamp":1735154992000},"page":"63","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Chronic Low-Level IFN-\u03b3 Expression Disrupts Mitochondrial Complex I Activity in Renal Macrophages: An Early Mechanistic Driver of Lupus Nephritis Pathogenesis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2205-9700","authenticated-orcid":false,"given":"Heekyong R.","family":"Bae","sequence":"first","affiliation":[{"name":"Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"Center for Food and Nutritional Genomics, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8918-3995","authenticated-orcid":false,"given":"Su-Kyung","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"Center for Food and Nutritional Genomics, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Yoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"Center for Food and Nutritional Genomics, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5194-7023","authenticated-orcid":false,"given":"Yeo Jin","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"Center for Food and Nutritional Genomics, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2155-892X","authenticated-orcid":false,"given":"Suntae","family":"Kim","sequence":"additional","affiliation":[{"name":"Omixplus, LLC., Gaithersburg, MA 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3118-5111","authenticated-orcid":false,"given":"Howard A.","family":"Young","sequence":"additional","affiliation":[{"name":"Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MA 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Young","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"Center for Food and Nutritional Genomics, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"Center for Beautiful Aging, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gerasimova, E.V., Popkova, T.V., Gerasimova, D.A., and Kirichenko, T.V. 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