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

• eIF3d and eIF3e promote synthesis of the mitochondrial ETC and respiration
• eIF3 deficiency leads to glycolytic switch, oxidative stress, and reduced lifespan
• eIF3e promotes the synthesis of ETC proteins through a 5′ UTR-mediated mechanism
• eIF3 subunits interact with mRNAs encoding ETC proteins

SummaryThe multi-subunit eukaryotic translation initiation factor eIF3 is thought to assist in the recruitment of ribosomes to mRNA. The expression of eIF3 subunits is frequently disrupted in human cancers, but the specific roles of individual subunits in mRNA translation and cancer remain elusive. Using global transcriptomic, proteomic, and metabolomic profiling, we found a striking failure of Schizosaccharomyces pombe cells lacking eIF3e and eIF3d to synthesize components of the mitochondrial electron transport chain, leading to a defect in respiration, endogenous oxidative stress, and premature aging. Energy balance was maintained, however, by a switch to glycolysis with increased glucose uptake, upregulation of glycolytic enzymes, and strict dependence on a fermentable carbon source. This metabolic regulatory function appears to be conserved in human cells where eIF3e binds metabolic mRNAs and promotes their translation. Thus, via its eIF3d-eIF3e module, eIF3 orchestrates an mRNA-specific translational mechanism controlling energy metabolism that may be disrupted in cancer.

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