Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction.

Summary

Cardiomyocyte-specific ACC1/2 deletion elevated FAO, depleted linoleic acid–derived cardiolipin, impaired ETC activity, and caused dilated cardiomyopathy. FAO inhibitors (etomoxir, oxfenicine) restored cardiolipin and ETC function and prevented heart failure, indicating that stimulating cardiac FAO may be harmful.

Key Findings

• ACC1/2 double-knockout mice exhibited constitutively elevated FAO and developed dilated cardiomyopathy and heart failure.
• Lipidomics showed marked cardiolipin depletion due to reduced linoleic acid, impairing ETC activity and mitochondrial function.
• FAO inhibition with etomoxir or oxfenicine restored cardiolipin, normalized ETC activity, and prevented cardiac dysfunction.

Clinical Implications

Therapies that indiscriminately boost cardiac FAO may be detrimental; conversely, selective FAO modulation restoring cardiolipin homeostasis could be cardioprotective and merits translational evaluation.

Limitations

• Findings are in murine models; human translational relevance requires validation
• Potential off-target effects of FAO inhibitors like etomoxir need careful consideration

Future Directions

Translate to human myocardium studies (biopsies, iPSC-CMs) to validate cardiolipin dynamics; evaluate selective FAO modulators and cardiolipin-stabilizing strategies in large-animal and early-phase trials.