The heart is the organ responsible for pumping blood and supplying nutrients and oxygen to all organs and cells of the body. The cells charged with these functions are the cardiomyocytes which require large amounts of energy. It is known that every single day the heart burns roughly 20 times its weight in the form of the molecular energy source, known as ATP, to pump approximately 8000 kg of blood. Therefore any failure in the supply of energy to the heart results decreases the organ’s pumping capacity, leading to heart failure and eventually death.
The major part of the energy necessary for cellular activity is provided by mitochondria. These cellular structures act as cell power houses, producing energy from the metabolism of organic fuels, including sugars, lipids and amino acids. Lack of a substrate or a failure in the coordinated biochemical processes of energy production has lethal consequences for the cell, and in the case of cardiomyocytes, for the patient. Now, a study led by researchers at the CNIC has shown how a defect in a vital mitochondrial process in heart cells specifically causes a type of dilated cardiomyopathy, a heart condition that in humans leads in most cases to heart disease and premature death. The team state their findings demonstrate that metabolic strategies based on diet are sufficient to restore correct heart function, opening the possibility of future treatments for patients with this disease. The study is published in the journal Science.
Previous studies show that dilated cardiomyopathy is a common disease in which the heart enlarges and loses contractile strength. In most cases, the disease causes heart failure and in terminal phases a heart transplant is required to avoid death. Although the condition can develop at any age, it is most common in people aged 40 to 50 years and affects between 3 to 10 people per 100,000 of the general population. There are currently no specific treatments, and it is therefore essential to understand the underlying mechanisms. Recent studies show that in healthy people, cardiomyocytes consume much more fatty acids than sugars because of the higher energy content of lipids; a situation reversed in heart failure patients. This was thought to be a defense mechanism, however, it has been hypothesized that the prolonged use of glucose by cardiomyocytes may instead be the cause of disease progression. The current study shows the key role of the protein YME1 in the regulation of the number, type and shape of mitocondria, and demonstrates that its absence induces a metabolic defect typical of patients with heart disease.
The current study fed a high-fat diet to mice with the mitochondrial defect to force the heart cells to consume more fatty acids than sugars, and thus ‘bypass’ the mitochondrial defect. Results show that the high-fat diet or ablating YME1 in skeletal muscle restored normal cell metabolism and that despite the presence of the mitochondrial defect the heart regained its normal function. Data findings show that this approach impedes disease development and increases the lifespan of mice with the mitochondrial defect.
Results show that adult myocardial function depends on balanced mitochondrial fusion and fission, maintained by processing of the dynamin-like guanosine triphosphatase OPA1 by the mitochondrial YME1 and OMA1 proteins. The group validated this via cardiac-specific ablation of YME1 in mice which activated OMA1 and accelerated OPA1 proteolysis, which triggered mitochondrial fragmentation and altered cardiac metabolism; this caused dilated cardiomyopathy and heart failure. Data findings show that cardiac function and mitochondrial morphology were rescued by Oma1 deletion, which prevented OPA1 cleavage. Therefore, the team state that unprocessed OPA1 is sufficient to maintain heart function, OMA1 is a critical regulator of cardiomyocyte survival, and mitochondrial morphology and cardiac metabolism are intimately linked.
The lab explain that the prevention of dilated cardiomyopathy in a mouse model by feeding a high-fat diet signals an advance in the understanding of the mechanisms involved in heart disease and has implications for the future development of treatments for this condition. They go on to conclude that their results confirm the need to dedicate more resources to basic research that advances knowledge of biological systems at the molecular level, in order to understand them better and thus be able to resolve the problems that arise in patients.
The team surmise that they are cautious in the interpretation of these results as it is known that a fat rich diet is a threat to health because it increases the incidence of atherosclerosis. They go on to add that the possibility that such a diet might be beneficial in certain cases of heart disease is very provocative and attractive. For the future, the researchers state that much translational research needs to be done before these results can be considered definitive and recommend that this multicenter research program should continue.
Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.
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