A Transcript-Specific eIF3 Complex Mediates Global Translational Control of Energy Metabolism

Area of Science:

• Molecular Biology
• Cellular Metabolism
• Cancer Research

Background:

• The eukaryotic translation initiation factor 3 (eIF3) complex plays a crucial role in initiating protein synthesis by aiding ribosome recruitment to messenger RNA (mRNA).
• While eIF3 subunit expression is often altered in human cancers, the precise functions of individual subunits in mRNA translation and their specific roles in oncogenesis are not fully understood.
• Investigating these roles is critical for understanding cancer biology and identifying potential therapeutic targets.

Purpose of the Study:

• To elucidate the specific functions of individual eIF3 subunits in mRNA translation and cellular metabolism.
• To investigate the impact of eIF3 subunit disruption on cellular respiration, energy balance, and aging.
• To determine if the observed metabolic regulatory functions are conserved in human cells and relevant to cancer.

Main Methods:

• Global transcriptomic, proteomic, and metabolomic profiling of Schizosaccharomyces pombe cells lacking eIF3e and eIF3d.
• Analysis of mitochondrial electron transport chain component synthesis, respiration, oxidative stress, and aging markers.
• Assessment of metabolic shifts, including glucose uptake, glycolytic enzyme activity, and carbon source dependence.
• Investigation of human cell lines to confirm the conserved role of eIF3e in metabolic mRNA translation.

Main Results:

• Cells lacking eIF3e and eIF3d exhibited a significant defect in synthesizing mitochondrial electron transport chain components, leading to impaired respiration and increased oxidative stress.
• These cells showed premature aging phenotypes and compensated for the loss of respiratory function by switching to glycolysis, characterized by increased glucose uptake and upregulation of glycolytic enzymes.
• The study identified a conserved function in human cells, where eIF3e directly binds to metabolic mRNAs and promotes their translation, highlighting a specific mRNA translational control mechanism.
• The eIF3d-eIF3e module was identified as a key component orchestrating this mRNA-specific translational control of energy metabolism.

Conclusions:

• The eIF3d-eIF3e module of eukaryotic translation initiation factor 3 (eIF3) plays a critical role in regulating cellular energy metabolism through mRNA-specific translation.
• Disruption of this module leads to metabolic dysregulation, impacting respiration and promoting a shift towards glycolysis, with implications for cellular aging.
• This conserved mechanism suggests that alterations in eIF3 function, particularly the eIF3d-eIF3e module, may contribute to the metabolic reprogramming observed in human cancers.