Mitochondrial iron aggregation as a key contributor to Friedreich’s ataxia-associated cardiomyopathy

objective: Friedreich’s ataxia (FRDA) is a rare genetic disorder caused by a deficiency of the mitochondrial protein frataxin, which is essential for the assembly and regulation of iron-sulfur clusters. In addition to neurological dysfunction, many FRDA patients develop cardiac complications, which are a major cause of early mortality. As subcellular iron overload has been involved in FRDA-related cardiomyopathy, this study aimed to investigate the underlying mechanisms. Hypothesis: As the mitochondria are central to FRDA pathogenesis, we hypothesize that mitochondrial iron overload and associated structural abnormalities contribute to the development of FRDA-related cardiac dysfunction. Methods: Using male heart-specific frataxin-deficient mice (FRDA mice; Jackson Laboratory #029720; n=7-8) at 8-10 weeks old, we characterized the pathophysiological features of the heart in FRDA. Specifically, we assessed mitochondrial iron levels (non-heme iron; NHI) using colorimetric analysis, oxidative capacity (oxygen consumption rate; OCR) with an Oroboros O2k respirometer, oxidative stress via lipid peroxidation (malondialdehyde; MDA), and ultrastructure using electron microscopy. Results: Compared to wild-type mice, FRDA mice exhibited cardiac dysfunction, evidenced by a significantly increased heart-to-body mass ratio ( p <0.0001) and elevated cardiac hypertrophy markers, including atrial natriuretic peptide and brain natriuretic peptide gene expression ( p <0.0001). Mitochondrial NHI was significantly elevated in FRDA hearts ( p <0.01), whereas cytosolic NHI remained unchanged. Electron microscopy revealed notable iron aggregation in the cristae of cardiac mitochondria along with abnormal structural changes. In addition, mitochondrial iron overload and structural alteration were associated with mitochondrial oxidative stress, as indicated by significantly elevated mitochondrial lipid peroxidation (i.e., MDA; p <0.01), while whole-cell redox status remained unaltered ( p >0.05). Furthermore, mitochondrial function was markedly impaired in the hearts of FRDA mice, with significant reductions in both basal (state 4, complex I; p <0.001) and maximal (state 3, complex I+II; p <0.01) mitochondrial OCR compared to control mice. Conclusion: We propose that mitochondrial iron aggregation and related structural abnormalities contribute to FRDA-related cardiac failure, suggesting that targeting iron deposits may be a potential therapeutic strategy to mitigate FRDA cardiac pathogenesis. Further studies are needed to elucidate the mechanisms underlying the formation and reversal of iron aggregations in the FRDA heart. This study is supported in part by DOD/CDMRP HT94252410009, NIH NS121394, and UMass Lowell Seed Grant. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.