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The development and maintenance of optimal CD8\u207a T cell effector and memory responses depend on mitochondrial fitness, which can be compromised across multiple physiologic and pathologic conditions. However, how impaired mitochondrial fitness affect antiviral CD8\u207a T cell responses remains poorly understood. Here, we used a CD8\u207a T cell-specific TFAM-haploinsufficient mouse model to induce moderate mitochondrial stress without the severe mitochondrial dysfunction associated with complete TFAM loss, providing a genetically controlled model of mitochondrial perturbations relevant to physiologic conditions. TFAM insufficiency disrupted mitochondrial integrity and cellular bioenergetics and increased mitochondrial DNA and oxidative stress in CD8\u207a T cells. During primary influenza A virus (IAV) infection, TFAM-insufficient CD8\u207a T cells exhibited heightened cytotoxic activity and inflammatory responses associated with lung immunopathology, followed by progressive functional exhaustion, diminished antigen-specific responses, and impaired protective immunity. Consistent with the physiologic relevance of these findings, CD8\u207a T cells from older individuals exhibited reduced TFAM expression and mitochondrial function. Collectively, our findings demonstrate that moderate mitochondrial stress can alter the trajectory of antiviral CD8\u207a T cell responses, promoting pathogenic effector activity during acute infection while compromising subsequent protective immunity.<\/jats:p>","DOI":"10.64898\/2026.09.24.754254","type":"posted-content","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:20:10Z","timestamp":1790504410000},"source":"Crossref","is-referenced-by-count":0,"title":["TFAM Dependent Mitochondrial Fitness Limits CD8\u207a T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia"],"prefix":"10.64898","author":[{"given":"Zahrasadat","family":"Navaeiseddighi","sequence":"first","affiliation":[{"name":"Dept of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Shafat","family":"Hasan","sequence":"additional","affiliation":[{"name":"Dept of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, 610500, China"},{"name":"Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rutuparnna","family":"Mishra","sequence":"additional","affiliation":[{"name":"Dept of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Schmit","sequence":"additional","affiliation":[{"name":"Dept of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamanah","family":"Ahsan","sequence":"additional","affiliation":[{"name":"Dept of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily J","family":"Moser","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care & Sleep Medicine, College of Medicine, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junguk","family":"Hur","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob S.","family":"Yount","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection & Immunity, The Ohio State University. 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