Poster abstracts
Poster number 44 submitted by Jiali He
Deciphering the function and mechanisms of translation elongation factor eIF5A in cardiomyocytes under heart disease
Jiali He (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry), Peng Yao (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry)
Abstract:
Disrupted translation efficiency leads to protein misfolding and aggregation in post-mitotic cell types, such as neurons and cardiomyocytes (CMs), causing neurodegeneration and heart disease. To maintain optimal translation efficiency, translation elongation factors, including eIF5A (eukaryotic translation Initiation Factor 5A), are required. The evolutionarily conserved protein eIF5A is responsible for ribosomal decoding of consecutive proline codons (Pro-Pro) and other triplet codon motifs such as Arg-x-Lys, allowing ribosome readthrough of these natural ribosome stalling sites. However, whether eIF5A downregulation is linked with impaired translation elongation, leading to heart disease, remains unknown. To investigate the CM-specific effect of eIF5A deletion, we generated an Eif5a(fl/fl)Myh6(MCM) conditional knockout (cKO) mouse model. Following tamoxifen-induced CM-specific Eif5a gene deletion in adult mice, all Eif5a cKO mice did not survive beyond ~5 weeks. Echocardiography data indicated the development of heart failure during the final week with significantly reduced ejection fraction, cardiac output, and increased left ventricular mass. In line with the echo data, further heart histological measurements also confirmed CM hypertrophy by WGA staining and cardiac fibrosis by picrosirius red staining. RNA-seq and mass spectrometry dual-omics analysis on early-stage (2 weeks) and late-stage (4 weeks) Eif5a cKO hearts suggest reduced translation efficiency in a variety of stress-related biological processes, including regulation of autophagy, unfolded protein response, and ubiquitin-proteasome system, leading to disrupted proteostasis. Intriguingly, dual-omics results (confirmed by qPCR and WB) revealed that the integrated stress response was not activated in Eif5a cKO heart, implying the systematic paralysis of general cellular stress-coping pathways. Ribosome profiling (Ribo-seq) on late-stage Eif5a cKO hearts is ongoing to determine the direct and preferential mRNAs regulated by eIF5A. Taken together, the ablation of eIF5A in CMs leads to cardiac hypertrophy, fibrosis, heart failure, and eventual lethality, due to ribosome stalling and collisions accompanied by the inability of cellular stress response activation.
References:
1 Wu, J. et al. Glutamyl-Prolyl-tRNA Synthetase Regulates Proline-Rich Pro-Fibrotic Protein Synthesis During Cardiac Fibrosis. Circulation Research 127, 827-846 (2020). https://doi.org/doi:10.1161/CIRCRESAHA.119.315999
2 Di Fraia, D. et al. Altered translation elongation contributes to key hallmarks of aging in the killifish brain. Science 389, eadk3079 (2025). https://doi.org/10.1126/science.adk3079
3 Feng, W. et al. Loss of eEF1A2 (Eukaryotic Elongation Factor 1 A2) in Murine Myocardium Results in Dilated Cardiomyopathy. Circ Heart Fail 14, e008665 (2021). https://doi.org/10.1161/CIRCHEARTFAILURE.121.008665
Keywords: eIF5A, translation efficiency, heart failure