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Sirtuin 6—the guardian of a failing heart

In a study that could help us better understand heart failures, researchers from the Indian Institute of Science, Bengaluru, have investigated the role of a protein called sirtuin 6 in the process of energy generation from glucose in a failing heart. The study was published in the Journal of Cellular Physiology and supported by the Department of Biotechnology, Department of Science and Technology and The Council for Scientific and Industrial Research, New Delhi.

Our heart, which continuously pumps oxygenated blood to all parts of the body, needs tremendous energy to keep it going. Biomolecules, like fatty acids and glucose, act as the energy source by turning into energy-rich molecules of adenosine triphosphate (ATP). Perturbations in this energy generation process might result in a failing heart.

Sirtuins are a group of proteins which participate in and regulate many crucial processes of our body, including like lifespan and ageing. Scientists have shown that these proteins also play a role in cancer, obesity and insulin resistance. Mammals have seven types of sirtuins and sirtuin 6, in particular, has been shown to influence lifespan. For example, an experiment with mice showed that an increase in this protein extended their lifespan and an artificial reduction led to their death.

Glucose is the main source of energy for a failing heart. In the process of glucose metabolism, each glucose molecule breaks down to produce two pyruvate molecules. This process generates very little energy from the glucose molecule, as most it remains stockpiled in the pyruvate molecules. The pyruvate molecules need to enter into a series of reactions, called the tricarboxylic acid (TCA) cycle, to generate more energy.

In this study, the researchers examined the glucose metabolism in mice with a reduced level of sirtuin 6 in their body. They observed that lactate, the conjugate base of the lactic acid, accumulated in the hearts of these mice. This condition indicated that the energy generation from glucose was incomplete in mice with reduced sirtuin 6 as the pyruvate molecules do not move to the TCA cycle completely, and instead participate in the process of lactate production.

The researchers also tried to understand the complete molecular mechanism behind this process. Pyruvate dehydrogenase is an enzyme in our body which help the pyruvate to enter in the TCA cycle. However, in the presence of pyruvate dehydrogenase kinase, it is prevented from carrying out its function. The researchers observed that decreased levels of sirtuin 6 lead to a higher concentration of these kinase molecules. Interestingly, when the sirtuin 6 levels were increased, the levels of kinase molecules reduced, letting the pyruvate dehydrogenase to continue its function and generate energy.

The study establishes that sirtuin 6 plays a significant role in directing glucose molecules towards the TCA cycle for efficient energy production. “Sirtuin 6 seems to play a cardioprotective role. Our results indicate that if supplemented within physiological limits, it might be able to prevent cardiac metabolic dysfunction, a hallmark of impending heart failure”, say the researchers, explaining their findings.