An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress
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.
Authors
- Andrea Raimondi (ORCID: https://orcid.org/0000-0002-4563-386X)
- Chiara Riganti (ORCID: https://orcid.org/0000-0001-9787-4836)
- Fiorella Altruda
- Giampaolo Morciano (ORCID: https://orcid.org/0000-0002-5355-0845)
- Elisa Balmas (ORCID: https://orcid.org/0000-0002-4600-6809)
- Lorenzo Silengo
- Carlo Tacchetti (ORCID: https://orcid.org/0000-0003-4602-000X)
- Matteo Sorge (ORCID: https://orcid.org/0000-0002-0635-3654)
- Federica Zamporlini
- Alessandra Ghigo (ORCID: https://orcid.org/0000-0002-1193-5296)
- Pasquale Pagliaro
- Silvia Velasco (ORCID: https://orcid.org/0000-0003-0638-0932)
- Guido Tarone
- Enrico Moiso (ORCID: https://orcid.org/0000-0002-4405-8357)
- Saveria Femminò (ORCID: https://orcid.org/0000-0003-4644-0784)
- Mara Brancaccio (ORCID: https://orcid.org/0000-0003-2327-6846)
- Paola Antonia Corsetto (ORCID: https://orcid.org/0000-0003-3849-8548)
- Andrea Gallo
- Alessandro Bertero (ORCID: https://orcid.org/0000-0002-4919-9087)
- Nadia Raffaelli (ORCID: https://orcid.org/0000-0002-4458-1789)
- Paolo Pinton (ORCID: https://orcid.org/0000-0001-7108-6508)
- Nathan J. Sniadecki (ORCID: https://orcid.org/0000-0001-6960-4492)
- Emilio Hirsch (ORCID: https://orcid.org/0000-0002-9073-6024)
- Angela Maria Rizzo (ORCID: https://orcid.org/0000-0002-8582-0432)
- Mauro Sbroggió (ORCID: https://orcid.org/0000-0002-8266-661X)
- Rachele Stefanìa (ORCID: https://orcid.org/0000-0002-8556-8556)
- Giulia Savoré (ORCID: https://orcid.org/0009-0002-1940-4024)
- Cláudia Penna (ORCID: https://orcid.org/0000-0002-9696-0449)
- Gabrielle Nattenberg
- Davide Acquarone
- Emilia Turco
Institutions
- Marche Polytechnic University (IT)
- University of Milan (IT)
- California Institute for Regenerative Medicine (US)
- University of Ferrara (IT)
- 5T Torino (Italy) (IT)
- Maria Cecilia Hospital (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Turin (IT)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1038/s44321-024-00132-z
- Citations
- 6
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Compagnia di San Paolo
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- National Institutes of Health
- National Heart, Lung, and Blood Institute