Mitochondrial Defect and Heart Disease Link Found in Study

In a new study, researchers linked the protein YME1 with a proper mitochondrial function and its absence to the fragmentation of mitochondria in vivo, dysfunction of mitochondrial activity, and the consequent onset of dilated cardiomyopathy in mice. The researchers also showed that dietary changes can restore proper heart function. The research study, titled “Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice,” was published in the journal Science.

Mitochondria are extremely important organelles, responsible for the generation of most of the energy necessary for cellular activity. Any defects in the metabolism process, such as lack of substrate for energy production, or in one of the enzymes in the biochemical process ultimately lead to cell death. Poor energy production affects cardiomyocytes, the cells responsible for the contractile abilities of the heart, and can also cause serious heart defects. One of these heart pathologies is dilated cardiomyopathy, an incurable disease characterized by heart enlargement and loss of contractile strength, which can lead to heart failure and, in terminal cases, require a heart transplant.

To study the molecular players in mitochondrial function, scientists generated mice models of YME1L and OMA1, two mitochondrial proteases involved in the processing of dynamin-like guanosine triphosphatase (GTPase) OPA1, a critical step in mitochondrial function. The results showed that deletion of YME1L induced cleavage of OPA1 by the stress-induced OMA1, a process that ultimately leads to the development of dilated cardiomyopathy in mice. Deletion of OMA1, however, prevented this process and enabled normal mitochondrial and heart functions.

The research study also focused on the dietary and metabolic changes in the animal models. In healthy people, the major fuel used to produce energy by the cardiomyocytes is fatty acids, since these molecules contain more energy than sugar. However, in diseased people, the contrary occurs, a fact that researchers now theorize is related to disease progression and not to a defense mechanism, as previously thought. Researchers fed mice with the mitochondrial defect a high-fat diet to force the heart cells to metabolize these nutrients instead of sugar. This dietary change restored normal cell metabolism and correct heart function, a discovery with important implications in potential patient therapy.

Dr. Valentín Fuster, MD, General Director of the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), one of the research teams involved in the study, commented in a press release, “We know that a diet rich in fats is a threat to health because it increases the incidence of atherosclerosis. The possibility that such a diet might be beneficial in certain cases of heart disease is very provocative and attractive. However, much translational research needs to be done before these results can be considered definitive. Nonetheless, this multicenter research program should continue, and perhaps over the medium term we will be in a position to answer this question and perhaps eventually overthrow another established paradigm.”