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Fatigue is a symptom often associated with autoimmune diseases. Chronic inflammatory response and activated cell\u2010mediated immunity are associated with cardiovascular myopathies which can be driven by muscle weakness and fatigue. Thus, we hypothesize that immune dysfunction\u2010driven changes in myocyte mitochondria may play a critical role in fatigue\u2010related pathogenesis. We show that persistent low\u2010level expression of IFN\u2010\u03b3 in designated IFN\u2010\u03b3 AU\u2010Rich Element deletion mice (ARE mice) under androgen exposure resulted in mitochondrial and metabolic deficiencies in myocytes from male or castrated ARE mice. Most notably, echocardiography unveiled that low ejection fraction in the left ventricle post\u2010stress correlated with mitochondrial deficiencies, explaining how heart function decreases under stress. We report that inefficiencies and structural changes in mitochondria, with changes to expression of mitochondrial genes, are linked to male\u2010biased fatigue and acute cardiomyopathy under stress. Our work highlights how male androgen hormone backgrounds and active autoimmunity reduce mitochondrial function and the ability to cope with stress and how pharmacological blockade of stress signal protects heart function. These studies provide new insight into the diverse actions of IFN\u2010\u03b3 in fatigue, energy metabolism, and autoimmunity. \u00a9 2023 The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.<\/jats:p>","DOI":"10.1002\/path.6081","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T04:55:25Z","timestamp":1682571325000},"page":"276-288","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<scp>IFN<\/scp>\u2010\u03b3 and androgens disrupt mitochondrial function in murine myocytes"],"prefix":"10.1002","volume":"260","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6848-9274","authenticated-orcid":false,"given":"John M","family":"Fenimore","sequence":"first","affiliation":[{"name":"Cancer Innovation Laboratory, Center for Cancer Research National Cancer Institute  Frederick MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle A","family":"Springer","sequence":"additional","affiliation":[{"name":"Murine Phenotyping Core, National 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