Unregulated fatty acid oxidation in acetyl-CoA carboxylase-deficient mice depleted linoleic acid stores, leading to cardiolipin deficiency, mitochondrial dysfunction, and heart failure.
Excessive and unregulated fatty acid oxidation in the heart can deplete linoleic acid stores, leading to cardiolipin deficiency, mitochondrial dysfunction, and heart failure.
Fatty acid oxidation (FAO) provides the healthy heart with 60%-90% of its ATP, with the remainder coming from metabolism of glucose. Metabolic flexibility is key to heart function, ensuring an uninterrupted source of fuel. In heart failure, a shift from FAO to glucose-dependent metabolism occurs as disease progresses, supporting the widely held notion that fat is the optimal substrate in the heart. In this issue of the JCI, Kim et al. challenge this assumption. In studies of acetyl-CoA carboxylase-deficient (ACC-deficient) mice, they found that unregulated use of fat as a substrate led to cardiac damage. ACC-deficient mice developed cardiolipin deficiency as a result of excessive FAO depleting stores of linoleic acid, which is used as a substrate for cardiolipin maturation. The resulting mitochondrial dysfunction was associated with dilated cardiomyopathy and heart failure in these mice. The findings highlight potential for development of therapeutic strategies that balance energy sources and replenish cardiolipin levels.
Claypool et al. (Fri,) conducted a editorial in Heart failure. Acetyl-CoA carboxylase deficiency was evaluated. Unregulated fatty acid oxidation in acetyl-CoA carboxylase-deficient mice depleted linoleic acid stores, leading to cardiolipin deficiency, mitochondrial dysfunction, and heart failure.
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