EIF3e Deficiency Impedes Mouse Growth And Mitochondrial Function In Skeletal Muscle

Research background:As the largest and most complex eukaryotic translation initiation factor(eIF),eIF3 plays an important role in the process of canonical translation initiation and disease occurrence.Eukaryotic translation initiation factor 3,subunit e(eIF3e),a component of eIF3 complex,plays an important role in protein synthesis regulation,although its physiological functions are unknown.Our previous research on Schizosaccharomyces pombe cells revealed that a module consisting of eIF3e and its dimerization partner eIF3d promoted the synthesis of components of the mitochondrial electron transport chain.Lack of this eIF3 module led to respiratory defects,endogenous oxidative stress and premature aging,suggesting an important role of eIF3e mitochondrial function and homeostasis.With skeletal muscle cells being especially rich in mitochondria,loss of eIF3e might have an impact on skeletal muscle function.We addressed this possibility in a mouse model of eIF3e deficiency and explored potential molecular mechanisms involved.Methods:To understand the effect of eIF3e on mitochondrial function and the physiological importance of eIF3e,we used interfering RNA technology to knock down eIF3e in breast cancer cells and generated eIF3e knockout mice.We analyzed the effects of eIF3e on mitochondrial function at the cellular and organismal levels through biochemical and animal behavior experiments.Results:We found that after knocking down eIF3e in tissue culture cells,the content of electron transport chain components decreased,the expression level of mitochondrial intact membrane proteins was down-regulated,and a large number of broken mitochondria appeared.On the other hand,we found that homozygous eIF3e knockout mouse died at an early stage of development.However,compared with wildtype mice,eIF3e heterozygous knockout mice(eIF3e+/-)showed no significant changes in growth and fertility,but their body weights and the levels of eIF3e mRNA in tissues decreased.Notably,among the tissues and organs examined,skeletal muscle was the most significantly affected by the loss of eIF3e.Assays measuring animal grip strength and running endurance showed that the skeletal muscle function of eIF3e+/-mice was significantly reduced compared to wild-type mice.eIF3e+/-mice accumulate defective mitochondria and show severe ultrastructural damage to the sarcomere structure in skeletal muscle as seen by transmission electron microscopy.NADH-TR staining showed that NADH activity in gastrocnemius and quadriceps muscles of eIF3e+/-mice was weaker,and Complex I activity was greatly reduced.Conclusion:Our research indicate that eIF3e is an essential gene for normal growth and development in mice.In addition,eIF3e is critical for mitochondrial function and muscle health.