TY  - JOUR
AU  - Remes, Cristina
AU  - Khawaja, Anas
AU  - Pearce, Sarah F
AU  - Dinan, Adam M
AU  - Gopalakrishna, Shreekara
AU  - Cipullo, Miriam
AU  - Kyriakidis, Vasileios
AU  - Zhang, Jingdian
AU  - Dopico, Xaquin Castro
AU  - Yukhnovets, Olessya
AU  - Atanassov, Ilian
AU  - Firth, Andrew E
AU  - Cooperman, Barry
AU  - Rorbach, Joanna
TI  - Translation initiation of leaderless and polycistronic transcripts in mammalian mitochondria
JO  - Nucleic acids research
VL  - 51
IS  - 2
SN  - 0305-1048
CY  - Oxford
PB  - Oxford Univ. Press
M1  - FZJ-2023-02031
SP  - 891 - 907
PY  - 2023
AB  - The synthesis of mitochondrial OXPHOS complexes is central to cellular metabolism, yet many molecular details of mitochondrial translation remain elusive. It has been commonly held view that translation initiation in human mitochondria proceeded in a manner similar to bacterial systems, with the mitoribosomal small subunit bound to the initiation factors, mtIF2 and mtIF3, along with initiator tRNA and an mRNA. However, unlike in bacteria, most human mitochondrial mRNAs lack 5′ leader sequences that can mediate small subunit binding, raising the question of how leaderless mRNAs are recognized by mitoribosomes. By using novel in vitro mitochondrial translation initiation assays, alongside biochemical and genetic characterization of cellular knockouts of mitochondrial translation factors, we describe unique features of translation initiation in human mitochondria. We show that in vitro, leaderless mRNA transcripts can be loaded directly onto assembled 55S mitoribosomes, but not onto the mitoribosomal small subunit (28S), in a manner that requires initiator fMet-tRNAMet binding. In addition, we demonstrate that in human cells and in vitro, mtIF3 activity is not required for translation of leaderless mitochondrial transcripts but is essential for translation of ATP6 in the case of the bicistronic ATP8/ATP6 transcript. Furthermore, we show that mtIF2 is indispensable for mitochondrial protein synthesis. Our results demonstrate an important evolutionary divergence of the mitochondrial translation system and further our fundamental understanding of a process central to eukaryotic metabolism.
LB  - PUB:(DE-HGF)16
C6  - 36629253
UR  - <Go to ISI:>//WOS:000910085600001
DO  - DOI:10.1093/nar/gkac1233
UR  - https://juser.fz-juelich.de/record/1007362
ER  -