How heart failure disrupts the cell’s powerhouse

Investigations in Japan have uncovered some molecular mechanisms behind mitochondrial dysfunction in chronic heart failure.

Chronic heart failure causes the cell’s power plants to malfunction, in part due to the overconsumption of an important intermediate compound in energy production. Supplementing the diet to compensate for this could prove to be a promising strategy for the treatment of heart failure. The results were published in the journal PNAS by scientists and colleagues from Hokkaido University in Japan.

Mitochondria are small organelles found in almost all cells and are responsible for converting carbohydrates, fats and proteins into energy to fuel biochemical reactions. Chronic heart failure is known to be associated with mitochondrial dysfunction, but how this occurs at the molecular level is still unknown.

A research team consisting of molecular biologist Hisataka Sabe (Hokkaido University), cardiovascular medicine specialists Shingo Takada (Hokkaido University and Hokusho University) and Shintaro Kinugawa (Kyushu University) and their colleagues studied the biochemical processes which occur in mice with chronic heart failure caused by surgically blocking off part of the blood supply to their heart. They specifically looked at heart cells outside the boundaries of dead tissue.

They found a significant reduction in a compound called succinyl-CoA, which is an intermediate in the cell’s tricarboxylic acid cycle. This cycle, which occurs inside the mitochondria, plays an important role in the breakdown of organic molecules to release energy.

Further investigations revealed that this reduction in succinyl-CoA levels was at least partly caused by its overconsumption for heme synthesis, which is essential for mitochondrial oxidative phosphorylation. This latter process is necessary to transfer and synthesize energy transport and storage molecules by the mitochondria.

Adding a compound called 5-aminolevulinate (5-ALA) acid to mice’s drinking water immediately after cutting off the blood supply to part of the heart significantly improved their heart function, treadmill running ability rolling and their survival. At the molecular level, it enhanced the oxidative phosphorylation capacity of heart muscle mitochondria and appeared to restore their succinyl-CoA levels.

Further research is needed to clarify other factors involved in reduced levels of mitochondrial succinyl-CoA in heart failure. For example, scientists have found evidence that succinyl-CoA can also be overused in mitochondria affected by heart failure to break down ketones for energy. But further investigations are needed to understand why this might be happening and if there really is a direct link between the two.

“Our results deepen the understanding of the detailed metabolic changes that occur in chronic heart failure and could contribute to the development of more natural disease prevention and treatment,” the team members say. “Furthermore, a combination of nutritional interventions that can correct the metabolic distortions that occur in chronic heart failure – as this study reveals – and currently used therapeutic drugs could be very effective in treating this disease.”

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Materials provided by Hokkaido University. Note: Content may be edited for style and length.

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