A mitochondrial long-chain fatty acid oxidation defect leads to uncharged tRNA accumulation and activation of the integrated stress response in the mouse heart

Ranea-Robles, P.; Pavlova, N. N.; Bender, A.; Stauffer, B.; Yu, C.; Thompson, C. B.; Argmann, C.; Puchowicz, M. A.; Houten, S. M.

doi:10.1101/2021.05.13.443905

bioRxiv · 10.1101/2021.05.13.443905

A mitochondrial long-chain fatty acid oxidation defect leads to uncharged tRNA accumulation and activation of the integrated stress response in the mouse heart

Ranea-Robles, P.·Pavlova, N. N.·Bender, A.·Stauffer, B.·Yu, C.·Thompson, C. B.·Argmann, C.·Puchowicz, M. A.·Houten, S. M.

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Abstract

The heart relies mainly on mitochondrial fatty acid {beta}-oxidation (FAO) for its high energy requirements. Cardiomyopathy and arrhythmias can be severe complications in patients with inherited defects in mitochondrial long-chain FAO, reinforcing the importance of FAO for cardiac health. However, the pathophysiological mechanisms that underlie the cardiac abnormalities in long-chain FAO disorders remain largely unknown. Here, we investigated the cardiac transcriptional adaptations to the FAO defect in the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse. We found a prominent activation of the integrated stress response (ISR) mediated by the eIF2/ATF4 axis in both fed and fasted states, accompanied by a reduction in cardiac protein synthesis during a short period of food withdrawal. Notably, we found an accumulation of uncharged tRNAs in LCAD KO hearts, consistent with a reduced availability of cardiac amino acids, in particular, glutamine. We replicated the activation of the cardiac ISR in hearts of mice with a muscle-specific deletion of carnitine palmitoyltransferase 2 deletion (Cpt2M-/-). Our results show that perturbations in amino acid metabolism caused by long-chain FAO deficiency impact cardiac metabolic signaling, in particular the ISR, and may play a role in the associated cardiac pathology.

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Ranea-Robles, P., Pavlova, N. N., Bender, A., Stauffer, B., Yu, C., Thompson, C. B., Argmann, C., Puchowicz, M. A., Houten, S. M.. 2021-05-15. A mitochondrial long-chain fatty acid oxidation defect leads to uncharged tRNA accumulation and activation of the integrated stress response in the mouse heart. https://doi.org/10.1101/2021.05.13.443905

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