新陈代谢调整的内在机制促进了心脏对压力的恢复能力。

IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EMBO Molecular Medicine Pub Date : 2024-09-13 DOI:10.1038/s44321-024-00132-z
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
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引用次数: 0

摘要

要找到保护心脏的有效方法,确定心脏复原力的分子机制至关重要。心脏通过脂肪酸氧化产生生理水平的 ROS,但应激事件会增加 ROS,导致线粒体功能障碍和心脏功能损伤。Melusin 是一种肌肉特异性伴侣蛋白,在应激过程中对心肌代偿性重塑是必需的。我们在此报告了 Melusin 在线粒体中的定位,它与线粒体三功能蛋白(脂肪酸氧化的关键酶)结合并降低其活性。通过研究小鼠和人类诱导多能干细胞衍生的心肌细胞,我们发现 Melusin 可减少心肌中的脂质氧化,并在稳态、压力过载和多柔比星治疗期间限制 ROS 的产生,从而防止线粒体功能障碍。因此,在压力刺激下同时使用脂质氧化抑制剂曲美他嗪治疗可限制 ROS 的积累,防止长期心脏功能障碍。这些发现揭示了心脏代谢调节的生理机制,并证明及时限制脂质代谢是提高心脏抗应激能力的一种潜在治疗策略。
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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.
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来源期刊
EMBO Molecular Medicine
EMBO Molecular Medicine 医学-医学:研究与实验
CiteScore
17.70
自引率
0.90%
发文量
105
审稿时长
4-8 weeks
期刊介绍: EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)
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