{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T21:47:34Z","timestamp":1789681654931,"version":"4.0.1"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to investigate mitochondrial dysfunction and its role in the pathogenesis of Fabry disease (FD) by analyzing circulating cell-free DNA (ccf-DNA) in patients with FD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Sixty-six FD patients and 21 healthy controls (ctrls) were enrolled. Levels of plasma mitochondrial- (ccf-mtDNA) and nuclear-derived ccf-DNA (ccf-nDNA) were quantified by quantitative reverse-transcription PCR (RT-qPCR), and 14 inflammatory cytokines were measured in treatment-na\u00efve patients. Associations among ccf-DNA levels, cytokine profiles, disease biomarkers, and clinical markers were analyzed, with subgroup analyses stratified by sex, genotype, clinical subtype, and disease severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Treatment-na\u00efve patients exhibited significantly higher ccf-mtDNA (\n                      <jats:italic>z<\/jats:italic>\n                      =\u20134.530,\n                      <jats:italic>P<\/jats:italic>\n                      -adj&amp;lt;0.001) and mtDNA\/nDNA ratio (\n                      <jats:italic>z<\/jats:italic>\n                      =\u20132.613,\n                      <jats:italic>P<\/jats:italic>\n                      -adj=0.014) compared with ctrls. In the long-term enzyme replacement therapy (ERT) group (&amp;gt; 12 months), ccf-mtDNA copy number remained elevated (\n                      <jats:italic>z<\/jats:italic>\n                      =\u20133.141,\n                      <jats:italic>P<\/jats:italic>\n                      -adj=0.006), whereas the mtDNA\/nDNA ratio did not differ significantly (\n                      <jats:italic>z<\/jats:italic>\n                      =\u20131.013,\n                      <jats:italic>P<\/jats:italic>\n                      -adj=0.311). No differences in ccf-nDNA were observed between treatment-na\u00efve patients or the long-term ERT group compared with ctrls. Receiver operating characteristic analysis demonstrated the strong diagnostic performance of ccf-mtDNA (area under the curve=0.860), with 70% sensitivity and 91% specificity at an optimal cut-off value of 1,793,188.04 copies. Both ccf-mtDNA and mtDNA\/nDNA ratio correlated positively with inflammatory cytokines including interleukin-17F and tumor necrosis factor-\u03b2, with stronger associations observed in male patients with classic FD. No correlations were observed with disease duration, \u03b1-galactosidase A activity, plasma globotriaosylsphingosine or clinical markers after adjustment for age and sex. Similarly, ccf-DNA measures did not differ significantly by sex,\n                      <jats:italic>GLA<\/jats:italic>\n                      mutation type (truncated\n                      <jats:italic>vs<\/jats:italic>\n                      . non-truncated), FD subtype (classic\n                      <jats:italic>vs<\/jats:italic>\n                      . non-classic), or across subgroups defined by disease severity or organ involvement (high\n                      <jats:italic>vs<\/jats:italic>\n                      . low MSSI, with or without hypertrophic cardiomyopathy, with or without chronic kidney disease, mild\n                      <jats:italic>vs<\/jats:italic>\n                      . severe white matter lesions, with or without neuralgia, or mild\n                      <jats:italic>vs<\/jats:italic>\n                      . severe pain).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Mitochondrial dysfunction, reflected by elevated ccf-mtDNA, is implicated in FD pathogenesis and may be linked to inflammatory activation. ccf-mtDNA represents a promising diagnostic biomarker for FD, potentially offering an additional therapeutic target when combined with ERT.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1706045","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T06:53:44Z","timestamp":1767768824000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Elevated circulating cell-free mitochondrial DNA in fabry disease: insights into inflammatory 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