Molecular mechanisms behind mitochondrial dysfunction in chronic heart failure

Chronic heart failure induces dysfunction in the cell’s powerhouses, partly caused by an excess of an essential intermediate compound in energy production. Compensating for this by supplementing the diet could be a potential technique for treating heart failure. Hokkaido University researchers and associates in Japan published their findings in the journal PNAS.

Molecular mechanisms behind mitochondrial dysfunction in chronic heart failure

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Mitochondria are tiny organelles found in nearly all cells that convert carbs, lipids, and proteins into energy to power biochemical processes. Chronic heart failure has been linked to mitochondrial dysfunction, although much remains unknown about how this occurs at the molecular level.

A team of researchers led by molecular biologist Hisataka Sabe (Hokkaido University), cardiovascular medicine specialists Shingo Takada (Hokkaido University and Hokusho University), and Shintaro Kinugawa (Kyushu University) investigated the biochemical processes that take place in mice with chronic heart failure caused by surgically blocking a portion of the blood supply to their hearts. They focused on cardiac cells, not within the confines of dead tissue.

Researchers observed a significant decrease in succinyl-CoA, a molecule that acts as an intermediate in the cell’s tricarboxylic acid cycle. This cycle, which occurs within mitochondria, is critical in the breakdown of organic molecules to release energy.

Further research established that the overuse of succinyl-CoA for synthesizing heme, which is necessary for mitochondrial oxidative phosphorylation, was at least partially to blame for this decrease in succinyl-CoA levels. This latter mechanism requires mitochondria to transport and synthesize energy-carrying and storing molecules.

Introducing 5-aminolevulinate acid (5-ALA) to mice’s drinking water soon after cutting off blood supply to a portion of the heart enhanced their cardiac function, treadmill running capability, and survival. It increased the oxidative phosphorylation capacity of heart muscle mitochondria and seemed to replenish their succinyl-CoA levels at the molecular level.

Further research is needed to clarify other factors involved in reducing mitochondrial succinyl-CoA levels in heart failure. For example, scientists found evidence that succinyl-CoA may also be overconsumed in heart failure-affected mitochondria to break down ketones as an energy source. But more investigations are needed to understand why this might happen and whether there is a direct link between the two.

The researchers say, “Our results further the understanding of the detailed metabolic changes that occur in chronic heart failure and could contribute to the development of more natural prevention and treatment for the condition.”

In addition, a combination of nutritional interventions that can correct the metabolic distortions that occur in chronic heart failure—as revealed in this study—and currently used therapeutic drugs could be very effective in the treatment of this disease,” concluded the experts.

Journal reference:

Takada, S., et al. (2022) Succinyl-CoA-based energy metabolism dysfunction in chronic heart failure. Proceedings of the National Academy of Sciences of the United States of America.


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