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This study was undertaken to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function, and to evaluate the consequences for fibroblast activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>TFAM expression was analyzed by immunofluorescence and Western blotting. The effects of TFAM knockout were investigated in cultured fibroblasts and in murine models of bleomycin\u2010induced skin fibrosis, bleomycin\u2010induced lung fibrosis, and skin fibrosis induced by overexpression of constitutively active transforming growth factor \u03b2 type I receptor (TGF\u03b2R\u0399).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TFAM expression was down\u2010regulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The down\u2010regulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mitochondrial DNA (mtDNA), accumulation of deletions in mtDNA, metabolic alterations with impaired oxidative phosphorylation, and release of the mitokine GDF15. Normal fibroblasts subjected to long\u2010term, but not acute, exposure to TGF\u03b2 mimicked SSc fibroblasts, with down\u2010regulation of TFAM and accumulation of mitochondrial damage. Down\u2010regulation of TFAM promoted fibroblast activation with up\u2010regulation of fibrosis\u2010relevant Gene Ontology terms in RNA\u2010Seq, partially in a reactive oxygen species\u2013dependent manner. Mice with fibroblast\u2010specific knockout of Tfam were prone to fibrotic tissue remodeling, with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and overexpression of constitutively active TGF\u03b2RI. TFAM knockout fostered Smad3 signaling to promote fibroblast activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGF\u03b2 and associated mitochondrial damage induce transcriptional programs that promote fibroblast\u2010to\u2010myofibroblast transition and drive tissue fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42033","type":"journal-article","created":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T09:32:25Z","timestamp":1637573545000},"page":"871-881","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis"],"prefix":"10.1002","volume":"74","author":[{"given":"Xiang","family":"Zhou","sequence":"first","affiliation":[{"name":"Friedrich\u2013Alexander University Erlangen\u2013Nuremberg and University Hospital Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuong","family":"Trinh\u2010Minh","sequence":"additional","affiliation":[{"name":"Friedrich\u2013Alexander University Erlangen\u2013Nuremberg and University Hospital Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuong","family":"Tran\u2010Manh","sequence":"additional","affiliation":[{"name":"Friedrich\u2013Alexander University Erlangen\u2013Nuremberg and University Hospital Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9768-2049","authenticated-orcid":false,"given":"Andreas","family":"Gie\u00dfl","sequence":"additional","affiliation":[{"name":"Friedrich\u2013Alexander University Erlangen\u2013Nuremberg and University Hospital Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Bergmann","sequence":"additional","affiliation":[{"name":"Friedrich\u2013Alexander University Erlangen\u2013Nuremberg and University Hospital Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea\u2010Hermina","family":"Gy\u00f6rfi","sequence":"additional","affiliation":[{"name":"Friedrich\u2013Alexander University Erlangen\u2013Nuremberg and University Hospital Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8740-9615","authenticated-orcid":false,"given":"Georg","family":"Schett","sequence":"additional","affiliation":[{"name":"Friedrich\u2013Alexander University Erlangen\u2013Nuremberg and University Hospital Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7408-9333","authenticated-orcid":false,"given":"J\u00f6rg H. 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