Researchers discover molecular mechanisms behind mitochondrial dysfunction in chronic heart failure

Researchers discover molecular mechanisms behind mitochondrial dysfunction in chronic heart failure

Research in Japan has uncovered some molecular mechanisms of mitochondrial dysfunction in chronic heart failure.

Chronic heart failure leads to dysfunction of cellular power plants, in part due to excessive consumption of an important intermediate in energy production. Compensatory nutritional supplementation may prove to be a promising strategy for treating heart failure. The results were published in the journal PNAS by scientists and colleagues at Hokkaido University in Japan.

Mitochondria are small organelles found in almost every cell and are responsible for converting carbohydrates, fats and proteins into energy to power biochemical reactions. It is known that chronic heart failure is associated with mitochondrial dysfunction, but how this occurs at the molecular level is still largely unknown.

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

They found a significant reduction in a compound called succinyl-CoA, which is an intermediary in the cell's tricarboxylic acid cycle. This cycle, which occurs in the mitochondria, plays an important role in breaking down organic molecules to release energy.

Further investigation revealed that this reduction in succinyl-CoA levels was caused, at least in part, by its excessive consumption for the synthesis of heme, which is essential for mitochondrial oxidative phosphorylation. This latter process is required to transfer and synthesize energy-carrying and storage molecules through mitochondria.

Adding a compound called 5-aminolevulinic acid (5-ALA) to mice's drinking water immediately after cutting off blood supply to part of the heart significantly improved their heart function, running performance and survival. At the molecular level, it improved 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 reducing mitochondrial succinyl-CoA levels in heart failure. The scientists found evidence that succinyl-CoA can also be taken in too much in mitochondria affected by heart failure in order to break down ketones as an energy source. However, more research is needed to understand why this might be happening and whether there really is a direct connection between the two.

“Our results advance understanding of the detailed metabolic changes that occur in chronic heart failure and could contribute to the development of more natural prevention and treatment of the disease,” say the team members. "In addition, a combination of nutritional interventions that can correct the metabolic disturbances that occur in chronic heart failure - as shown in this study - and currently used therapeutic medications could be very effective in treating this disease."

Source:

Hokkaido University

Reference:

Takada, S., et al. (2022) Succinyl-CoA-based energy metabolism disorder in chronic heart failure. PNAS. doi.org/10.1073/pnas.2203628119.

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