Mitochondria are small intracellular organelles responsible for converting carbohydrates, fats and proteins into energy to power biochemical reactions. Mitochondrial dysfunction is closely associated with the development of heart failure, and metabolic dysfunction, including that of the tricarboxylic acid (TCA) cycle, which is a core metabolic pathway for producing ATP, is known as the main cause. Recent studies have shown that the selective accumulation of succinate, an intermediate of the TCA cycle, during acute ischemia in the mouse heart is a major cause of reperfusion injury. On the other hand, how the TCA cycle and its associated metabolic pathways respond to chronic heart failure remains largely unclear. Chronic heart failure causes mitochondria to dysfunction, in part due to overconsumption of an important intermediary compound in energy production. Supplementing the diet to compensate for this could prove a promising strategy for treating heart failure.
Chronic heart failure (CHF) is known to be associated with mitochondrial dysfunction, but much is still unknown about how this happens at the molecular level. A japanese research team of molecular biologist, cardiovascular medicine specialists 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 and found a significant reduction in a metabolite called succinyl-CoA, which is an intermediary in the TCA cycle. This cycle happening inside mitochondria release energy by oxidizing metabolic substrates. Further investigations revealed that this reduction 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 oxygen and transferring energy-carrying molecules by mitochondria.
At the molecular level, it improved the oxidative phosphorylation capacity of heart muscle mitochondria and appeared to restore their succinyl-CoA levels. The researchers analyzed whether the protein levels of enzymes associated with succinyl-CoA were altered. The E1 component of the 2-oxoglutarate dehydrogenase (OGDH) complex that generates succinyl-CoA from α-ketoglutarate (α-KG) was found significantly increased in mice with heart ischemia compared to healthy mice. There was also a significant increase in the protein levels of glutamate dehydrogenase 1 (GDH1), which catalyzes the reversible reaction of glutamate to α-KG. On the other hand, there was no statistical difference in the protein levels of propionyl-CoA carboxylase alpha (PCCA) and methylmalonyl-CoA mutase (MMCM), which synthesize succinyl-CoA from specific fatty acids and aminoacids. Then scientists hypothesized that a reason for the decrease in succinyl-CoA levels in infarctuated mice may be the excessive consumption of succinyl-CoA for heme synthesis.
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. The molecule 5-ALA is an intermediate in the pathway from succinyl-CoA to heme synthesis and is particulartly efficient in the bone marrow cells, where it is used to produce hemoglobin. Taken together, 5-ALA might be effective, to certain extents, for the prevention of HF progression after heart infarction. Moreover, these results support the hypothesis that the decreased succinyl-CoA level in sick mice is owed, at least in part, to the excessive consumption of succinyl-CoA for heme synthesis. Further research is needed to clarify other factors involved in reducing mitochondrial succinyl-CoA levels in heart failure. For example, the scientists found also evidence that succinyl-CoA may also be overconsumed in heart failure-affected mitochondria in order to break down ketones as a source of energy.
Indeed, it would be normal for cells with impaired oxygen supply to enhance heme and hemoprotein synthesis in order to utilize most the available oxygen even while lacking. But researchers deem that more investigations are needed to understand why this might happen and whether there really is a direct link between the two. The findings were published in the journal Proceedings of National Academic Sciences (PNAS).
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Takada S et al. PNAS 2022; 119(41):e2203628119.
Martin JL, Costa ASH et al. Nat Metab. 2019; 1:966–974
Bertero E., Maack C. Nat Rev Cardiol. 2018; 15:457–470.
Okonko DO, Shah AM. Nat Rev Cardiol. 2015; 12:6–8.
Dott. Gianfrancesco Cormaci
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