BREAKING! Japanese Scientists Discover That 5-ALA Supplementation Could Reverse Or Prevent Mitochondrial Dysfunction That Causes Chronic Heart Failure!
A new study involving murine models by researchers from Hokkaido University Graduate School of Medicine, Sapporo-Japan has found that 5-ALA (of 5-aminolevulinic acid) could reverse or prevent mitochondrial dysfunction that causes chromic heart failure!
5-Aminolevulinic acid is a porphyrin precursor used to treat actinic keratosis of the face, scalp, and upper extremities, as well as to visualize a glioma. 5-ALA is currently licensed by the U.S.FDA for the photodynamic treatment of dermatological conditions such as actinic keratoses, squamous and basal cell carcinomas and, more recently, in the tumour resection of high-grade gliomas. It is also available as a supplement.
The study findings also have relevance in the current COVID-19 pandemic, where it has already been found that the SARS-CoV-2 virus is capable of causing mitochondria damage and dysfunction and also the fact that heart failure is often a common occurrence as a result of COVID-19 infections and damages the virus causes directly or indirectly to the heart muscles, tissues and even cardiac functions. (refer to studies listed at the end of the article)
Heart failure (HF) is a leading cause of death and repeated hospitalizations and typically involves cardiac mitochondrial dysfunction.
To date however, the underlying mechanisms largely remain elusive.
The study team using a mouse model in which myocardial infarction (MI) was induced by coronary artery ligation, showed the metabolic basis of mitochondrial dysfunction in chronic HF.
Four weeks after ligation, MI mice showed a significant decrease in myocardial succinyl-CoA levels, and this decrease impaired the mitochondrial oxidative phosphorylation (OXPHOS) capacity. Heme synthesis and ketolysis, and protein levels of several enzymes consuming succinyl-CoA in these events, were increased in MI mice, while enzymes synthesizing succinyl-CoA from α-ketoglutarate and glutamate were also increased.
In addition, it was found that the ADP-specific subunit of succinyl-CoA synthase was reduced, while its GDP-specific subunit was almost unchanged.
Interestingly, administration of 5-aminolevulinic acid, an intermediate in the pathway from succinyl-CoA to heme synthesis, appreciably restored succinyl-CoA levels and OXPHOS capacity and prevented HF progression in MI mice.
Past studies also suggested the presence of succinyl-CoA metabolism abnormalities in cardiac muscles of HF patients.
The study findings showed that changes in succinyl-CoA usage in different metabolisms of the mitochondrial energy production system is characteristic to chronic HF, and although similar alterations are known to occur in healthy conditions, such as during strenuous exercise, they may often occur irreversibly in chronic HF leading to a decrease in succinyl-CoA. Consequently, nutritional interventions compensating the succinyl-CoA consumption are expected to be promising strategies to treat HF.
The study findings were published in the peer reviewed journal: PNAS (Proceedings of the National Academy of Sciences)
This detailed investigations in Japan have uncovered some molecular mechanisms behind mitochondrial dysfunction in chronic heart failure.
ypically, chronic heart failure as a result of the cell's powerhouse dysfunction and in part due to overconsumption of an important intermediary compound in energy production.
According to the study team, supplementing the diet to compensate for this could prove a promising strategy for treating heart failure.
The mitochondria are small organelles found in almost every cell and are responsible for converting carbohydrates, fats and proteins into energy to power biochemical reactions. Chronic heart failure is known to be associated with mitochondrial dysfunction, but much is still unknown about how this happens at the molecular level.
The study team consisting of molecular biologist Dr Hisataka Sabe (Hokkaido University), cardiovascular medicine specialists Dr Shingo Takada (Hokkaido University and Hokusho University) and Dr Shintaro Kinugawa (Kyushu University) and their colleagues studied the biochemical processes that occur in mice with chronic heart failure caused by surgically blocking part of the blood supply to their hearts. They specifically looked at heart cells outside the boundaries of dead tissue.
The study team found a significant reduction in a compound called succinyl-CoA, which is an intermediary in the cell's tricarboxylic acid cycle. This cycle, which happens inside mitochondria, plays an important role in breaking down organic molecules to release energy.
Subsequent detailed investigations revealed that this reduction of succinyl-CoA levels was at least in part caused by its overconsumption for the synthesis of heme, which is essential for mitochondrial oxidative phosphorylation. This latter process is needed for transferring and synthesizing energy-carrying and storage molecules by mitochondria.
Interestingly, adding a compound called 5-aminolevulinate acid (5-ALA) to the drinking water of mice immediately after cutting off the blood supply to part of the heart significantly improved their heart function, treadmill running capacity and survival.
Also, at the molecular level, it improved the oxidative phosphorylation capacity of heart muscle mitochondria and appeared to restore their succinyl-CoA levels.
The stud team said that further research is warranted to clarify other factors involved in reducing mitochondrial succinyl-CoA levels in heart failure. For example, the scientists found evidence that succinyl-CoA may also be overconsumed in heart failure-affected mitochondria in order to break down ketones as a source of energy. But more investigations are needed to understand why this might happen and whether there really is a direct link between the two.
Co-corresponding author Dr Hisataka Sabe from the Department Molecular Biology, Hokkaido University Graduate School of Medicine, told Thailand Medical News
, "Our study findings provides further 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."
For more on Chronic Heart Failure And COVID-19
, keep on logging to Thailand Medical News