title: Mammalian elongation factor 4 regulates mitochondrial translation essential for spermatogenesis.
abstract: Elongation factor 4 (EF4) is a key quality-control factor in translation. Despite its high conservation throughout evolution, EF4 deletion in various organisms has not yielded a distinct phenotype. Here we report that genetic ablation of mitochondrial EF4 (mtEF4) in mice causes testis-specific dysfunction in oxidative phosphorylation, leading to male infertility. Deletion of mtEF4 accelerated mitochondrial translation at the cost of producing unstable proteins. Somatic tissues overcame this defect by activating mechanistic (mammalian) target of rapamycin (mTOR), thereby increasing rates of cytoplasmic translation to match rates of mitochondrial translation. However, in spermatogenic cells, the mTOR pathway was downregulated as part of the developmental program, and the resulting inability to compensate for accelerated mitochondrial translation caused cell-cycle arrest and apoptosis. We detected the same phenotype and molecular defects in germline-specific mtEF4-knockout mice. Thus, our study demonstrates cross-talk between mtEF4-dependent quality control in mitochondria and cytoplasmic mTOR signaling.
authors.affiliation: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Bai
authors.affiliation: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Dejiu
authors.initials: D
authors.lastname: Zhang
authors.affiliation: University of Chinese Academy of Sciences, Beijing, China.|State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Han
authors.affiliation: Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Key Laboratory of Food Nutrition and Safety, Ministry of Education, School of Food Engineering and Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Xintao
authors.initials: X
authors.lastname: Cao
authors.affiliation: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Zilei
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Fugen
authors.initials: F
authors.lastname: Shangguan
authors.affiliation: Key Laboratory of Food Nutrition and Safety, Ministry of Education, School of Food Engineering and Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: University of Chinese Academy of Sciences, Beijing, China.|State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qin
mesh_terms: D016475:3T3 Cells; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D007248:Infertility, Male / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D010085:Oxidative Phosphorylation; D010448:Peptide Initiation Factors / Q000737:chemistry / Q000502:physiology*; D014176:Protein Biosynthesis; D021381:Protein Transport; D012270:Ribosomes / Q000201:enzymology; D013091:Spermatogenesis; D013737:Testis / Q000201:enzymology / Q000473:pathology
chemical_list: D010448:Peptide Initiation Factors