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Mitochondrial dysfunction has been reported in FD, but the role of mitochondrial stress remains unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate whether mitochondrial unfolded protein response (mtUPR) related markers associate with phenotypic variability and correlates with disease severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We measured intracellular heat-shock protein 60 (Hsp60) expression by western blotting in fibroblasts and peripheral blood mononuclear cells (PBMCs). In the clinical cohort, intracellular Hsp60 was measured in PBMC whole-cell lysates from 27 FD patients (14 males, 13 females). Serum fibroblast growth-factor-21 and growth differentiation-factor-15 were measured in 35 patients. Clinical outcomes included Mainz Severity Score Index, Age-Adjusting Severity Score, estimated glomerular filtration rate, and left-ventricular mass index (LVMI).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Hsp60 showed variability, with sex-specific associations. In males, higher Hsp60 correlated with lower LVMI (r\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u2009\u22120.82,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.01) and preserved renal function in late-onset patients (r\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20090.89,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.006). In females, higher Hsp60 associated with higher LVMI (r\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20090.66,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.045) and greater clinical severity. Male patients had elevated growth differentiation-factor-15 vs controls (935 vs 559\u2009pg\/ml,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002). Both mitokines correlated with age and disease severity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>mtUPR related markers exhibit sex- and genotype-specific patterns associated with disease severity, suggesting that mitochondrial stress contributes to phenotypic heterogeneity and support further longitudinal evaluation of Hsp60, FGF-21 and GDF-15 as candidate biomarkers of disease burden and treatment response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04461-9","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:23:58Z","timestamp":1782797038000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial stress markers associate with phenotypic variability in Fabry disease"],"prefix":"10.1186","volume":"21","author":[{"given":"Lucia","family":"Lavalle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hibba","family":"Kurdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Moreno","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Muczynski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Heales","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derralynn","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"issue":"1","key":"4461_CR1","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/1750-1172-5-30","volume":"5","author":"DP Germain","year":"2010","unstructured":"Germain DP. 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