Early mitophagy defects and impaired mitochondrial energy metabolism drive target organ damage progression: Lessons from the Fabry heart
Increasing evidence supports a pathogenic role for impaired energy metabolism in organ damage. Genetic diseases provide opportunities to investigate these mechanisms, as exemplified by Fabry disease (FD), caused by an α-galactosidase A (GLA) deficiency and globotriaosylceramide (Gb3) accumulation, with cardiomyopathy as the leading cause of death. Beyond Gb3 storage, impaired energy metabolism may contribute to cardiomyopathy. Here, we demonstrate mitochondrial dysfunction in FD heart and its therapeutic targeting. Using a humanized FD mouse model (R301Q-Tg/GLA knockout), embryonic fibroblasts, and neonatal and adult cardiomyocytes, we found impaired mitophagy and mitochondrial respiration, increased reactive oxygen species, and a vicious cycle aggravating lysosomal dysfunction. These defects progressed with age, causing accumulation of dysfunctional mitochondria, energetic failure, apoptosis, cardiac hypertrophy, and diastolic dysfunction. L-arginine, promoting NO/PGC-1α-dependent mitochondrial rescue, prevented cardiac abnormalities. Our findings identify mitochondrial dysfunction as a key driver of FD cardiomyopathy and reveal the lysosome-mitochondria axis as a targetable pathway in FD and beyond.
Authors
- Eleonora Riccio (ORCID: https://orcid.org/0000-0002-5379-1104)
- Guido Iaccarino (ORCID: https://orcid.org/0000-0002-8997-835X)
- Jessica Gambardella (ORCID: https://orcid.org/0000-0001-5563-3153)
- Cinzia Perrino (ORCID: https://orcid.org/0000-0002-2274-0048)
- Gaetano Santulli (ORCID: https://orcid.org/0000-0001-7231-375X)
- Daniela Sorriento (ORCID: https://orcid.org/0000-0002-1599-4509)
- Stefania D’Apice (ORCID: https://orcid.org/0000-0002-4151-5153)
- Antonio Pezone (ORCID: https://orcid.org/0000-0002-0068-6212)
- Alessandro Viti (ORCID: https://orcid.org/0000-0003-0567-404X)
- Shivangi Pande
- Fahimeh Varzideh (ORCID: https://orcid.org/0000-0003-2423-0831)
- Antonio Pisani (ORCID: https://orcid.org/0000-0003-0241-8323)
- Roberta Avvisato (ORCID: https://orcid.org/0000-0002-6583-0393)
- Roberta Paolillo (ORCID: https://orcid.org/0000-0002-5170-517X)
- Nella Prevete (ORCID: https://orcid.org/0000-0002-0186-5431)
- Antonella Fiordelisi
- Valeria D’Argenio (ORCID: https://orcid.org/0000-0001-9273-3698)
- Pietro Campiglia (ORCID: https://orcid.org/0000-0002-1069-2181)
- Letìzia Spinelli (ORCID: https://orcid.org/0000-0002-9774-6268)
- Antonietta Buonaiuto
- Junichi Sadoshima (ORCID: https://orcid.org/0000-0003-3724-4132)
- Federica Andrea Cerasuolo
- Antonio Bianco
- Eduardo Sommella
- Giovanna Giuseppina Altobelli
Institutions
- Rutgers, The State University of New Jersey (US)
- University of Salerno (IT)
- City University of New York (US)
- San Raffaele University of Rome (IT)
- Federico II University Hospital (IT)
- CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) (IT)
- University of Florence (IT)
- University of Naples Federico II (IT)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-10-26
- DOI
- https://doi.org/10.1016/j.celrep.2026.118183
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Regione Campania
- National Heart, Lung, and Blood Institute