Poster abstracts
Poster number 100 submitted by Yui Kawakami
Loss of EIF5A Disrupts Cardiac and Skeletal Muscle Proteostasis and Causes Early onset Cardiomyopathy and Lethality
Yui Kawakami (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, New York, USA 14642), Joseph DeTraglia (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, New York, USA 14642), Peng Yao (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, New York, USA 14642)
Abstract:
A progressive decline in protein homeostasis is a hallmark of aging, contributing to the onset of many age-related diseases. Translation elongation factors play a critical role in preventing these disruptions by supporting an efficient decoding of challenging ribosome-stalling codon sequences. For example, the evolutionarily conserved translation elongation factor, eIF5A, has been shown to support translational efficiency and proteome stability, especially under high translational demand. Our lab generated the Eif5a CkmmCre -driven cardiomyocyte and skeletal muscle cells-specific KO model. Homozygous deletion of eIF5A driven by CkmmCre (active at ~E13.5) led to early postnatal lethality, with death occurring between postnatal(P)24 and P26. Echocardiographic analysis revealed a significant increase in left ventricular mass at endpoint compared to CkmmCre controls, along with a robust decrease in ejection fraction, fractional shortening, and stroke volume, indicating progressive cardiac dysfunction in the absence of eIF5A protein. At the early stage (P16), dual-omics analysis revealed that eIF5A deletion induces some widespread changes in protein levels that are not reflected at the transcription level, indicating increased translation efficiency for these mRNAs potentially involved in compensatory responses. Interestingly, proteins involved in the ubiquitination pathway, including ubiquitin-specific proteases such as Otub2 and Usp32, showed significantly elevated translation efficiency; additionally, components related to stress response pathways, such as Socs2, had increased translation efficiency, potentially suggesting eIF5A's importance in sustaining proteostasis via its crosstalk with the ubiquitin-proteasome pathway and its importance in the cellular stress responsive pathways. These changes also involved other pathways, such as mitochondrial function and extracellular matrix remodeling, all of which are critical for maintaining cardiac structure and function. Findings in this study could offer potential novel therapeutic targets in cardiac diseases and generalizable more broadly to other organ aging and pathogenic processes.
References:
Subbaiah KCV, Wu J, Tang WHW, Yao P. Ciclopirox Inhibition of eIF5A Hypusination Attenuates Fibroblast Activation and Cardiac Fibrosis. J Cardiovasc Dev Dis. 2023 Jan 29;10(2):52. doi: 10.3390/jcdd10020052. PMID: 36826549; PMCID: PMC9963048.
Keywords: eIF5A, Translation efficiency , Ubiquitination