Long-chain fatty acid β-oxidation (FAO) deficiency disturbs amino acid metabolism and interferes with cardiac metabolic signaling in long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mice, researchers reported. The LCAD KO mouse mimics prominent symptoms of human long chain fatty acid oxidation disorders (LCFAOD), such as very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) and carnitine palmitoyltransferase 2 (CPT2) deficiency.
Pablo Ranea-Robles, PhD, first-author of the publication “A mitochondrial long-chain fatty acid oxidation defect leads to uncharged tRNA accumulation and activation of the integrated stress response in the mouse heart.”, presented the results of the study at the INFORM Lecture Series, virtually held on September 20, 2021. A preprint version of the publication is available on bioRxiv.
The analysis of heart samples from LCAD KO mice, collected after overnight food withdrawal, revealed more than 2000 differentially expressed genes (DEGs). Using a fold-change cut-off value of 1.5, the authors found 1032 upregulated and 1302 downregulated genes.
Read about LCFAOD etiology
The most upregulated gene in LCAD KO’s heart was asparagine synthetase, a canonical target of the activating transcription factor 4 (ATF4). In addition, the authors found another 51 ATF4 target genes upregulated.
ATF4 is a key mediator of the integrated stress response (ISR). “This is an adaptative response to stress, different types of stresses,” explained Dr. Ranea-Robles, who earned his PhD in biomedicine from the University of Barcelona in Spain. For instance, it reprograms translation in response to nutrient stress.
Therefore, the study authors went further to investigate the ISR in heart samples from LCAD KO mice. They found increased cardiac protein levels of phosphorylated eukaryotic initiation factor-2α (eIF2α [S51]), ATF4, and asparagine synthetase. Together with additional molecular findings, these led the authors to conclude that LCAD deficiency led to nutrient stress which, consequently, activated the ISR through the eIF2α/ATF4 axis. Moreover, they found that decreased nutrient availability might impair protein synthesis in the heart, an effect likely to be mediated by the ISR.
In addition, they showed that defects in long-chain FAO can lead to the selective uncharging of several transfer RNAs (tRNAs) in LCAD KO hearts. They observed an upregulation in tRNA aminoacylation pathway in both LCAD KO and the CPT2 KO hearts, which suggests the existence of a common pathophysiological mechanism in long-chain FAO defects.
“This is not only the first report on tRNA charging in the mouse heart, this is also the first time that uncharging of tRNAs is demonstrated in a disease model,” the authors said.
Despite being cautious when questioned about the clinical implications of these findings for LCFAOD patients, Dr. Ranea-Robles believes this study provides great insight into how FAO defects impact cardiac metabolism and supports the use of ISR modulators in future investigations.
A mitochondrial long-chain fatty acid oxidation defect leads to uncharged tRNA accumulation and activation of the integrated stress response in the mouse heart. Presented at: INFORM Lecture Series: September 20, 2021; Virtual.
Ranea-Robles P, Pavlova NN, Bender A, et al. A mitochondrial long-chain fatty acid oxidation defect leads to uncharged tRNA accumulation and activation of the integrated stress response in the mouse heart. bioRxiv. Published online June 1, 2021. doi:10.1101/2021.05.13.443905