Abstract Body: Background: Friedreich’s ataxia (FA) is an autosomal disorder caused by deficiency in frataxin (FXN), a nuclear-encoded mitochondrial protein that is essential for iron-sulfur (Fe-S) cluster synthesis. While cardiomyopathy is a leading cause of mortality in FA patients, the mechanism of disease pathogenesis in the heart remains poorly understood.
Methods: We collected post-mortem cardiac tissues from FA patients and established a longitudinal mouse model of acute Fxn deficiency. We performed single nucleus RNA sequencing to elucidate the cellular composition and dysregulated molecular pathways in FA hearts.
Results: Mice developed progressive LV hypertrophy starting at 3 weeks following Fxn depletion. At 12 weeks, the LV posterior wall dimension significantly increased in Fxn deficient mice (1.02±0.12 vs 0.75±0.03 mm, p = 1E-05, n = 12). Histological analyses revealed significant cardiac fibrosis in both mice (4.8±2.3% vs 1.2±0.8%, p = 1.4E-11, n = 7) and human (25.7±13.8% vs 4.3±4.6%, p = 2E-03, n = 8) and significant iron accumulation in mouse hearts (2.11±1.97% vs 0.04±0.02%, p = 1E-06, n = 14). Cell composition analysis demonstrated significant reduction of pericytes in both human (7.0±2.6% vs 18.7±6.8%, p = 7.4E-03, n = 3) and mice (7.3±1.1% vs 10.0±1.1%, p = 0.02, n = 5), reduction of cardiomyocytes in human only (4.4±2.3% vs 49.0±15.8%, p = 5.9E-06, n = 3), and increase in myeloid cells in mice only (14.9±3.9% vs 9.1±1.3%, p = 0.02, n = 5). We identified a new myeloid cell state, reticuloendothelial macrophages (REM), in both human (24.8±14/4% vs 1.7±1.7% of myeloid cells, p = 0.02, n = 3) and mice (45.1±11.9% vs 3.7±0.9% of myeloid cells, p = 9.4E-7, n = 5) FA hearts. REM proportion significantly correlates with cardiac fibrosis in mice (r = 0.49, p = 5.3E-07). REM cells are enriched in ferritin, ferroportin, and heme oxygenase 1 (Hmox1), an enzyme that breaks down heme and is upregulated in response to antioxidant stress.
Conclusions: We observed similar cellular pathologies in human and mouse FA hearts, including profound cardiac fibrosis, significant reduction in pericytes and increase in REM cells. REM cells showed high expression of iron metabolism genes, suggesting that this could be an adaptation to iron accumulation in the heart.