The role of Yme1l in the progression of heart failure. Nutritional approaches for prevention
Título (trad.)
El papel de Yme1l en el desarrollo de la insuficiencia cardiaca. Terapias nutricionales para su prevenciónAutor (es)
Villena Gutiérrez, RocíoEntidad
UAM. Departamento de Bioquímica; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Fecha de edición
2023-01-26Materias
Biología y Biomedicina / BiologíaNota
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 26-01-2023Esta tesis tiene embargado el acceso al texto completo hasta el 26-07-2024
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Resumen
Heart failure (HF) with reduced ejection fraction is prevalent in leading to reduced life expectancy, poor quality of life and is responsible for a large proportion of healthcare costs. Dilated cardiomyopathy (DCM) is one of the main etiologies responsible for HF, especially in young and middle-aged patients. DCM is defined by ventricular chamber enlargement and systolic impairment leading to progressive HF. Nowadays, there is a lack of specific therapies for DCM able to reverse this condition.
Our group has been a pioneer in demonstrating that imbalanced mitochondrial dynamics in cardiomyocytes results in an overt DCM phenotype. We generated a mouse with genetic ablation of the mitochondrial protease YME1L in cardiomyocytes (cYKO), which results in incorrect OPA1 processing and ultra-fragmented mitochondria in the heart in adulthood. These mice display normal cardiac function until week 30 of age, where a progressive DCM phenotype with reduced lifespan is shown. Moreover, cardiomyocytes display a metabolic switch characterized by preferential use of glucose as a metabolic substrate.
This thesis project focusses firstly on the causality of the protease YME1L during DCM development. Unexpectedly, we found mitochondrial abnormalities (larger size and increased respiration) in a subclinical stage of the disease, when no macroscopic cardiac phenotype is apparent. We demonstrate an autophagy impairment underlying Yme1l cardiac-genetic ablation. This is accompanied by increased ER stress, apparently mediated by dysregulation of Ca2+ handling. Interestingly, these defects are seen in animals before onset of the disease.
Secondly, our data show that a fat-restricted diet was able not only to prevent HF but also extends the lifespan of cYKO mice. We studied the molecular mechanisms underlying this cardioprotective effect. The mitochondrial ultrastructure indicates a restored mitochondrial number and enlarged size, which is not accompanied by enhanced mitochondrial respiration. Moreover, autophagy defects were still present. However, we speculate that better modulation of ER Ca2+ handling under this diet could be involved in enhanced cardiac performance.
These intriguing data call for a comprehensive evaluation of the mechanisms leading to HF prevention and to identifying a diet that could then be translated into clinics
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Google Scholar:Villena Gutiérrez, Rocío
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