ArticleCardiovascular research2022
A mitochondrial long-chain fatty acid oxidation defect leads to transfer RNA uncharging and activation of the integrated stress response in the mouse heart.
Article in Cardiovascular research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 19 citations in OpenAlex.
- PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy.Nature cardiovascular research · 2026Article
- Review
- The impact of lipid metabolism on ferroptosis in myocardial ischemia-reperfusion injury.Apoptosis : an international journal on programmed cell death · 2025Review
- Chios Mastic Gum Extract Enhances Antioxidant Defense in Zebrafish.International journal of molecular sciences · 2025Article
- A Multiomic Network Approach to Uncover Disease Modifying Mechanisms of Inborn Errors of Metabolism.Journal of inherited metabolic disease · 2025Article
- CPT1A/HIF-1α positive feedback loop induced fatty acid oxidation metabolic pathway contributes to the L-ascorbic acid-driven angiogenesis in breast cancer.Breast cancer research : BCR · 2025Article
- Tissue specific roles of fatty acid oxidation.Advances in biological regulation · 2025Review
- The Role of Short-Chain Fatty Acids in Myocardial Ischemia-Reperfusion Injury.Current nutrition reports · 2024Review
- Structural basis for expanded substrate specificities of human long chain acyl-CoA dehydrogenase and related acyl-CoA dehydrogenases.Scientific reports · 2024Article
- A review of fatty acid oxidation disorder mouse models.Molecular genetics and metabolism · 2024Review
- Structural Basis for Expanded Substrate SpeciResearch square · 2024Article
- Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome.Basic research in cardiology · 2023Article
- Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of Raptor in zebrafish.The Journal of biological chemistry · 2023Article
- Parkinson's Disease and the Heart: Studying Cardiac Metabolism in the 6-Hydroxydopamine Model.International journal of molecular sciences · 2023Article
- Cardiac Myocyte-Specific Overexpression of FASTKD1 Prevents Ventricular Rupture After Myocardial Infarction.Journal of the American Heart Association · 2023Article
- Cardiac Involvement in Mitochondrial Disorders.Current heart failure reports · 2023Review
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Authors and funding
11 authors at 5 institutions in 1 country.
Funding
Abstract
aimsCardiomyopathy and arrhythmias can be severe presentations in patients with inherited defects of mitochondrial long-chain fatty acid β-oxidation (FAO). The pathophysiological mechanisms that underlie these cardiac abnormalities remain largely unknown. We investigated the molecular adaptations to a FAO deficiency in the heart using the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse model. METHODS AND
resultsWe observed enrichment of amino acid metabolic pathways and of ATF4 target genes among the upregulated genes in the LCAD KO heart transcriptome. We also found a prominent activation of the eIF2α/ATF4 axis at the protein level that was independent of the feeding status, in addition to a reduction of cardiac protein synthesis during a short period of food withdrawal. These findings are consistent with an activation of the integrated stress response (ISR) in the LCAD KO mouse heart. Notably, charging of several transfer RNAs (tRNAs), such as tRNAGln was decreased in LCAD KO hearts, reflecting a reduced availability of cardiac amino acids, in particular, glutamine. We replicated the activation of the ISR in the hearts of mice with muscle-specific deletion of carnitine palmitoyltransferase 2.
conclusionsOur results show that perturbations in amino acid metabolism caused by long-chain FAO deficiency impact cardiac metabolic signalling, in particular the ISR. These results may serve as a foundation for investigating the role of the ISR in the cardiac pathology associated with long-chain FAO defects.Translational Perspective: The heart relies mainly on mitochondrial fatty acid β-oxidation (FAO) for its high energy requirements. The heart disease observed in patients with a genetic defect in this pathway highlights the importance of FAO for cardiac health. We show that the consequences of a FAO defect extend beyond cardiac energy homeostasis and include amino acid metabolism and associated signalling pathways such as the integrated stress response.
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