The study findings were published in the peer reviewed journal: PNAS (Proceedings of the National Academy of Sciences)
https://www.pnas.org/doi/full/10.1073/pnas.2203628119
In this study, using a well-established MI mouse model, we demonstrated that the selective decrease in myocardial succinyl-CoA levels is a prominent feature of chronic HF, and that this decrease is associated with a reduction in mitochondrial OXPHOS capacity.
Consistently, a recent report analyzing clinical heart specimens suggested the dysfunction of succinyl-CoA metabolism in HF patients (18). Moreover, our analyses demonstrated that the protein levels of several enzymes associated with succinyl-CoA metabolism, which may either increase or decrease succinyl-CoA levels, were changed substantially in chronic HF (Fig. 4G).
On the other hand, our results of 5-ALA administration to MI mice support the notion that excess heme synthesis in chronic HF is one cause that leads to a reduction in succinyl-CoA. However, most succinyl-CoA-associated metabolic pathways that were found to be altered in MI mice may be closely associated with each other, and it remains unknown as to what other changes are closely associated with the decreased succinyl-CoA levels.
In agreement with our mouse experiments, increased levels of ALAS1 mRNA and decreased levels of SUCLG1/SUCLA2 mRNA are observed in the myocardium of some HF patients (20, 21). Therefore, the molecular mechanism as to how these mRNA levels are altered in MI mice, as well as in HF patients, awaits clarification.
The myocardium of MI mice was also often found to have increased ketolysis, together with increased Oxct1 levels. Enhanced ketolysis indeed occurs in the failing hearts of patients, as mentioned above, and moreover, ketolysis in the heart occurs even in healthy conditions, such as during strenuous exercise (22), although it is not known whether Oxct1 levels are also altered.
The up-regulation of ketogenesis and β-OHB synthesis in the liver during strenuous exercise appears to be a strategy to supply β-OHB to the brain, as well as to the heart, skeletal muscles, and kidneys as an energy source, at times when blood glucose is greatly consumed. However, although enhanced ketolysis in the heart is a normal biological phenomenon, this can be disadvantageous for failing hearts, because enhanced ketolysis requires a large amount of succinyl-CoA, despite succinyl-CoA consumption being often increased for the synthesis of heme in failing hearts.
On the other hand, cardiac muscle can use fatty acids as an energy source, and it has been reported that blood levels of fatty acids are not particularly reduced in patients with HF or in mouse models (13, 23). The brain cannot take in fatty acids due to the blood–brain barrier. Furthermore, ketolysis in the heart may be a zero-sum game with respect to succinyl-CoA, because in ketolysis, succinyl-CoA is first consumed to synthesize acetoacetyl-CoA, which is then converted to acetyl-CoA and may be used to synthesize succinyl-CoA. Thus, the increased ketolysis in MI mice may or may not be causative to the decreased succinyl-CoA levels.
Why failing hearts predominantly use ketone bodies rather than fatty acids, and whether this is a simple remnant of a normal system or may have some potential advantages as a biological defense system, are issues that require clarification in the future.
In this study, we treated MI mice with 5-ALA alone, whereas in most previous studies, such as in neuroscience and in oncology, 5-ALA was administered in combination with iron-containing compounds, such as sodium ferrous citrate, to promote heme synthesis (24, 25). An abnormal increase in myocardial heme is thought to further exacerbate failing hearts, such as it may increase free heme (26). On the other hand, we have shown that 5-ALA alone can compensate considerably for the consumption of succinyl-CoA without further increasing heme in the myocardium of MI mice.
In summary, we demonstrated that nutritional intervention that compensates for the altered succinyl-CoA metabolism in chronic HF (i.e., 5-ALA administration) is a promising method to treat this disease, although our results also suggested that 5-ALA by itself might not be sufficient to effectively treat HF.
Therefore, our results, as well as a further understanding of the detailed metabolic changes that occur in chronic HF and the molecular mechanisms therein involved, will contribute to the development of HF therapeutics, particularly to the development of more natural treatments, as well as to the prevention of HF (27).
Succinyl-CoA is the most abundant acyl-CoA in the heart (28). Whether the histone acylations involved in epigenetic control (9) are altered in chronic HF should also be clarified in the future (29).
