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

Kim, C.-W.; Vale, G.; McDonald, J.; Dai, C.; Li, C.; Wang, Z. V.; Sharma, G.; Khemtong, C.; Malloy, C.; Deja, S.; Burgess, S.; Mitsche, M.; Horton, J. D.

doi:10.64898/2026.01.12.698694

bioRxiv · 10.64898/2026.01.12.698694

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

Kim, C.-W.·Vale, G.·McDonald, J.·Dai, C.·Li, C.·Wang, Z. V.·Sharma, G.·Khemtong, C.·Malloy, C.·Deja, S.·Burgess, S.·Mitsche, M.·Horton, J. D.

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Abstract

Cardiomyocytes primarily rely on fatty acid oxidation (FAO), which provides more than 70% of their energy. However, excessive FAO can disrupt cardiac metabolism by increasing oxygen demand and suppressing glucose utilization through the Randle cycle. Although inhibition of FAO has been investigated in heart failure, its overall therapeutic impact remains uncertain. To determine the consequences of enhanced FAO, we generated cardiomyocyte-specific ACC1 and ACC2 double-knockout (ACC dHKO) mice, which exhibit constitutively elevated FAO. ACC dHKO mice developed dilated cardiomyopathy and heart failure. Lipidomic analysis revealed marked depletion of cardiolipin caused by reduced linoleic acid, a direct consequence of excessive FAO. This cardiolipin deficiency impaired mitochondrial electron transport chain (ETC) activity, leading to mitochondrial dysfunction. Pharmacologic inhibition of FAO with etomoxir or oxfenicine restored cardiolipin levels, normalized ETC activity, and prevented cardiac dysfunction in ACC dHKO mice. These findings demonstrate that unrestrained FAO disrupts both lipid and energy homeostasis, culminating in heart failure in this model. Collectively, these results indicate that although FAO is essential for cardiac energy production, therapeutic strategies aimed at stimulating cardiac FAO may be detrimental rather than beneficial in heart failure.

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Kim, C.-W., Vale, G., McDonald, J., Dai, C., Li, C., Wang, Z. V., Sharma, G., Khemtong, C., Malloy, C., Deja, S., Burgess, S., Mitsche, M., Horton, J. D.. 2026-01-12. Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction. https://doi.org/10.64898/2026.01.12.698694

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