An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress.

Autor:	Sorge M; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy. matteo.sorge@unito.it., Savoré G; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Gallo A; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Acquarone D; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Sbroggiò M; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Velasco S; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Zamporlini F; Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, 60121, Italy., Femminò S; Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043, Italy., Moiso E; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Morciano G; Department of Medical Sciences, University of Ferrara, Ferrara, 44121, Italy.; Maria Cecilia Hospital, GVM Care and Research, Cotignola, 48033, Italy., Balmas E; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Raimondi A; Experimental Imaging Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, 20132, Italy., Nattenberg G; Departments of Mechanical Engineering, Bioengineering, and Laboratory Medicine and Pathology, Institute for Stem Cell and Regenerative Medicine, and Center for Cardiovascular Biology, University of Washington, Seattle, WA, 98109, USA., Stefania R; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Tacchetti C; Experimental Imaging Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, 20132, Italy., Rizzo AM; Department of Pharmacological and Biomolecular Sciences, University of Milan, Milano, 20133, Italy., Corsetto P; Department of Pharmacological and Biomolecular Sciences, University of Milan, Milano, 20133, Italy., Ghigo A; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Turco E; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Altruda F; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Silengo L; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Pinton P; Department of Medical Sciences, University of Ferrara, Ferrara, 44121, Italy.; Maria Cecilia Hospital, GVM Care and Research, Cotignola, 48033, Italy., Raffaelli N; Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, 60121, Italy., Sniadecki NJ; Departments of Mechanical Engineering, Bioengineering, and Laboratory Medicine and Pathology, Institute for Stem Cell and Regenerative Medicine, and Center for Cardiovascular Biology, University of Washington, Seattle, WA, 98109, USA., Penna C; Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043, Italy., Pagliaro P; Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043, Italy., Hirsch E; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Riganti C; Department of Oncology, University of Turin, Torino, 10126, Italy., Tarone G; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Bertero A; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy., Brancaccio M; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center 'Guido Tarone', University of Turin, Turin, 10126, Italy. mara.brancaccio@unito.it.
Jazyk:	angličtina
Zdroj:	EMBO molecular medicine [EMBO Mol Med] 2024 Oct; Vol. 16 (10), pp. 2450-2484. Date of Electronic Publication: 2024 Sep 13.
DOI:	10.1038/s44321-024-00132-z
Abstrakt:	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. (© 2024. The Author(s).)
Databáze:	MEDLINE
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