Calcium dysregulation amplifies fibrotic responses to TGFβ in human Friedreich's ataxia fibroblasts
- 1Weill Cornell Medicine
Abstract
Friedreich's ataxia (FA) is an inherited disease caused by loss of frataxin (FXN) and characterized by neurodegeneration and fatal cardiomyopathy. Cardiac fibrosis contributes to cardiomyopathy by stiffening the heart wall, yet the underlying mechanisms remain unknown. Here, we investigated pro-fibrotic predisposition in FA patient-derived fibroblasts, focusing on the role of cytosolic calcium (Ca) in TGF{beta}-driven fibroblast-to-myofibroblast transition (FMT). We found pro-fibrotic transcriptional priming in FA fibroblasts, alongside elevated expression of genes controlled by the Ca-responsive transcription factor NFAT. Upon FMT, FA myofibroblasts showed amplified induction of pro-fibrotic (CCN2, NOX4) and suppression of anti-fibrotic (CCN3) genes, which were inversely correlated with residual FXN. Mechanistically, FA fibroblasts exhibited elevated cytosolic Ca and strongly downregulated expression of the Na-Ca exchanger NCX1, which directly correlated with FXN. Furthermore, NCX1 inhibition in control fibroblasts recapitulated FA Ca phenotypes, whereas NCX1 transduction in FA fibroblasts normalized Ca dynamics and blunted CCN2 induction in FMT. These findings highlight NCX1 as a modulator of fibrotic reprogramming in FA and identify Ca dyshomeostasis as an intrinsic mechanism of fibrosis that could be targeted therapeutically.
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BibTeX
@misc{stepanova2026calcium,
title = {{Calcium dysregulation amplifies fibrotic responses to TGFβ in human Friedreich's ataxia fibroblasts}},
author = {A. Stepanova and H. Kawamata and G. Manfredi},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753166},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753166v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Calcium dysregulation amplifies fibrotic responses to TGFβ in human Friedreich's ataxia fibroblasts
AU - A. Stepanova
AU - H. Kawamata
AU - G. Manfredi
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753166
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753166v1
AB - Friedreich's ataxia (FA) is an inherited disease caused by loss of frataxin (FXN) and characterized by neurodegeneration and fatal cardiomyopathy. Cardiac fibrosis contributes to cardiomyopathy by stiffening the heart wall, yet the underlying mechanisms remain unknown. Here, we investigated pro-fibrotic predisposition in FA patient-derived fibroblasts, focusing on the role of cytosolic calcium (Ca) in TGF{beta}-driven fibroblast-to-myofibroblast transition (FMT). We found pro-fibrotic transcriptional priming in FA fibroblasts, alongside elevated expression of genes controlled by the Ca-responsive transcription factor NFAT. Upon FMT, FA myofibroblasts showed amplified induction of pro-fibrotic (CCN2, NOX4) and suppression of anti-fibrotic (CCN3) genes, which were inversely correlated with residual FXN. Mechanistically, FA fibroblasts exhibited elevated cytosolic Ca and strongly downregulated expression of the Na-Ca exchanger NCX1, which directly correlated with FXN. Furthermore, NCX1 inhibition in control fibroblasts recapitulated FA Ca phenotypes, whereas NCX1 transduction in FA fibroblasts normalized Ca dynamics and blunted CCN2 induction in FMT. These findings highlight NCX1 as a modulator of fibrotic reprogramming in FA and identify Ca dyshomeostasis as an intrinsic mechanism of fibrosis that could be targeted therapeutically.
ER -