How heart failure disrupts cellular motility

Japanese studies have revealed some of the molecular mechanisms
behind mitochondrial dysfunction in chronic heart failure.

Chronic heart failure leads to dysfunction of the cellular motility, in part due to excessive consumption of an important intermediate compound
during energy production.
Compensating for this deficiency by supplementing the diet may be a promising strategy
for treating heart failure.
The findings were published in the Proceedings of the National Academy of Sciences by scientists and colleagues at Hokkaido University in Japan
.

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

A team of molecular biologists Hisataka Sabe (Hokkaido University), cardiovascular medicine experts Shingo Takada (Hokkaido University and Hokusoku University) and Shintaro Kinugawa (Kyushu University) and their colleagues studied the biochemical processes
that occur in mice with chronic heart failure due to surgery to block part of the blood supply to the heart.
They specifically looked at heart cells
outside the boundaries of dead tissue.

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

Further studies have shown that the decrease in succinyl-CoA levels is due, at least in part, to excessive consumption of succinyl-CoA during the synthesis of heme, which is required for
mitochondrial oxidative phosphorylation.
The latter process is necessary
by mitochondria to transfer and synthesize molecules that carry energy and store energy.

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

Further research is needed to elucidate other factors
that reduce mitochondrial succinyl-CoA levels in heart failure.
For example, scientists have found evidence that succinyl-CoA may also be overconsumed in mitochondria affected by heart failure to break down ketones
as a source of energy.
But more investigation is needed to understand why this is happening and whether there really is a direct link
between the two.

"Our findings further deepen our understanding of the metabolic changes that occur in chronic heart failure and help develop more natural prevention and treatment
methods," team members said.
"In addition, as this study reveals, nutritional interventions that can correct metabolic distortions that occur in chronic heart failure, as well as currently used therapeutics, may be highly effective
in treating this disease.
"

Journal Reference:

1. Shingo Takada, Satoshi Maekawa, Takaaki Furihata, Naoya Kakutani, Daiki Setoyama, Koji Ueda, Hideo Nambu, Hikaru Hagiwara, Haruka Handa, Yoshizuki Fumoto, Soichiro Hata, Tomoka Masunaga, Arata Fukushima, Takashi Yokota, Dongchon Kang, Shintaro Kinugawa, Hisataka Sabe.
   Succinyl-CoA-based energy metabolism dysfunction in chronic heart failure.
   Proceedings of the National Academy of Sciences, 2022; 119 (41) DOI: 10.
   1073/pnas.
   2203628119