| Autor: |
Matteo Sorge, Giulia Savoré, Andrea Gallo, Davide Acquarone, Mauro Sbroggiò, Silvia Velasco, Federica Zamporlini, Saveria Femminò, Enrico Moiso, Giampaolo Morciano, Elisa Balmas, Andrea Raimondi, Gabrielle Nattenberg, Rachele Stefania, Carlo Tacchetti, Angela Maria Rizzo, Paola Corsetto, Alessandra Ghigo, Emilia Turco, Fiorella Altruda, Lorenzo Silengo, Paolo Pinton, Nadia Raffaelli, Nathan J Sniadecki, Claudia Penna, Pasquale Pagliaro, Emilio Hirsch, Chiara Riganti, Guido Tarone, Alessandro Bertero, Mara Brancaccio |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
EMBO Molecular Medicine, Vol 16, Iss 10, Pp 2450-2484 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
1757-4684 |
| DOI: |
10.1038/s44321-024-00132-z |
| Popis: |
Abstract Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overload and doxorubicin treatment, preventing mitochondrial dysfunction. Accordingly, the treatment with the lipid oxidation inhibitor Trimetazidine concomitantly with stressful stimuli limits ROS accumulation and prevents long-term heart dysfunction. These findings disclose a physiologic mechanism of metabolic regulation in the heart and demonstrate that a timely restriction of lipid metabolism represents a potential therapeutic strategy to improve cardiac resilience to stress. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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