Healthy cardiomyocytes (left panel) mainly use fatty acids as their energy source. To produce ATP, fatty acids are first converted into acylcarnitines, which are converted back to fatty-acyl-CoA and enter the β-oxidation cycle inside mitochondria. The resulting acetyl-CoAs then enter the citric acid cycle. In a mouse model of heart failure and in failing human hearts (right panel), cardiomyocytes depend more on ketones for energy. The ketone βOHB enters the mitochondrion where the enzyme BDH1 converts it into acetoacetate, whose products serve as substrates for the citric acid cycle. Both mice and humans with heart failure experience increased serum levels of βOHB, but in human cells βOHB and acylcarnitine levels go down. In mice, heart failure reduces the abundance of proteins involved in fatty acid oxidation. Both alterations suggest ketones are preferred over fatty acids in failing hearts.
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