eIF3 promotes early translation elongation to ensure mitochondrial homeostasis and skeletal muscle health

eIF3 is a multi-subunit complex with numerous functions in canonical translation initiation, including mRNA recruitment to the 40S ribosome, scanning for the start codon, and inhibition of premature 60S subunit joining . eIF3 was also found to interact with 40S and 60S ribosomal proteins and translation elongation factors , but a direct involvement in translation elongation has never been demonstrated. Using ribosome profiling, we found that eIF3 deficiency reduced early ribosomal elongation speed between codons 25 and 75 on a set of ∼2,700 mRNAs encoding proteins associated with mitochondrial and membrane functions, resulting in defective synthesis of their encoded proteins. To promote early elongation, eIF3 forms stable protein interactions with 80S ribosomes translating the first ∼60 codons and serves as a platform to recruit protein quality control factors, functions required for normal mitochondrial physiology. Accordingly, eIF3e knockout mice accumulate defective mitochondria in skeletal muscle and show a progressive decline in muscle strength with age. Hence, in addition to its canonical role in translation initiation, eIF3 interacts with 80S ribosomes to enhance, at the level of early elongation, the synthesis of proteins with membrane-associated functions, an activity that is critical for mitochondrial physiology and muscle health.