Mechanism of membrane-tethered mitochondrial protein synthesis

Itoh, Yuzuru; Andréll, Juni; Choi, Austin; Richter, Uwe; Maiti, Priyanka; Best, Robert B.; Barrientos, Antoni; Battersby, Brendan J.; Amunts, Alexey

doi:10.1126/science.abe0763

Cited by 86 publications

(108 citation statements)

References 61 publications

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“…3f ). At exit side of the ribosomal tunnel, we observe that mitoribosomal protein mL45 inserts its N-terminal tail into the tunnel, as observed for the non-translating mature mitoribosomes 29 , 30 , and reaches almost to the Obg domain of MTG2. Consequently, the two proteins sample virtually the entire length of the exit tunnel and may play a role in facilitating proper folding of proteins and rRNA elements forming the mitoribosomal nascent polypetide tunnel during mt-LSU maturation.…”

Section: Resultssupporting

confidence: 64%

“…Published structures of the mature human mitoribosome 30 ( PDB 6ZM6 ) and of a late assembly intermediate containing the ACP module 17 ( PDB 5OOL ) were used as initial models and docked into the cryo-EM maps using UCSF Chimera 44 . Composite models were assembled in PyMOL Molecular Graphics System, Version 2.1.5 (Schrödinger, LLC), followed by manual rebuilding of the proteins and nucleic acids using Coot 48 .…”

Section: Methodsmentioning

confidence: 99%

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Stepwise maturation of the peptidyl transferase region of human mitoribosomes

et al. 2021

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Mitochondrial ribosomes are specialized for the synthesis of membrane proteins responsible for oxidative phosphorylation. Mammalian mitoribosomes have diverged considerably from the ancestral bacterial ribosomes and feature dramatically reduced ribosomal RNAs. The structural basis of the mammalian mitochondrial ribosome assembly is currently not well understood. Here we present eight distinct assembly intermediates of the human large mitoribosomal subunit involving seven assembly factors. We discover that the NSUN4-MTERF4 dimer plays a critical role in the process by stabilizing the 16S rRNA in a conformation that exposes the functionally important regions of rRNA for modification by the MRM2 methyltransferase and quality control interactions with the conserved mitochondrial GTPase MTG2 that contacts the sarcin-ricin loop and the immature active site. The successive action of these factors leads to the formation of the peptidyl transferase active site of the mitoribosome and the folding of the surrounding rRNA regions responsible for interactions with tRNAs and the small ribosomal subunit.

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Section: Resultssupporting

confidence: 64%

Section: Methodsmentioning

confidence: 99%

Stepwise maturation of the peptidyl transferase region of human mitoribosomes

et al. 2021

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“…The human mitoribosome is highly proteinaceous, containing twice as much protein as RNA, and is largely associated with the inner membrane in order to facilitate co-translational insertion of OXPHOS proteins ( 24 ). These unique features make quantitative biochemical purification of mitoribosomes for the purpose of analyzing their translatomes more difficult than purification of cytosolic ribosomes ( 25 ).…”

Section: Resultsmentioning

confidence: 99%

Balanced mitochondrial and cytosolic translatomes underlie the biogenesis of human respiratory complexes

Soto

Couvillion

McShane

et al. 2021

Preprint

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Oxidative phosphorylation (OXPHOS) complexes consist of nuclear and mitochondrial DNA- encoded subunits. Their biogenesis requires cross-compartment gene regulation to mitigate the accumulation of disproportionate subunits. To determine how human cells coordinate mitochondrial and nuclear gene expression processes, we established an optimized ribosome profiling approach tailored for the unique features of the human mitoribosome. Analysis of ribosome footprints in five cell types revealed that average mitochondrial synthesis rates corresponded precisely to cytosolic rates across OXPHOS complexes. Balanced mitochondrial and cytosolic synthesis did not rely on rapid feedback between the two translation systems. Rather, LRPPRC, a gene associated with Leigh's syndrome, is required for the reciprocal translatomes and maintains cellular proteostasis. Based on our findings, we propose that human mitonuclear balance is enabled by matching OXPHOS subunit synthesis rates across cellular compartments, which may represent a vulnerability for cellular proteostasis.

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“…This interaction occurs via the long C-terminus of OXA1L/OXA1, in both humans and yeast [ 117 ]. Recently, a cryo-EM structure showed an association between human OXA1L and mitochondrial ribosomes in a native state, coupling protein synthesis and membrane delivery [ 118 ].…”

Section: Protein Translocationmentioning

confidence: 99%

Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration

Needs

Protasoni

Henley

et al. 2021

Life

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The fact that >99% of mitochondrial proteins are encoded by the nuclear genome and synthesised in the cytosol renders the process of mitochondrial protein import fundamental for normal organelle physiology. In addition to this, the nuclear genome comprises most of the proteins required for respiratory complex assembly and function. This means that without fully functional protein import, mitochondrial respiration will be defective, and the major cellular ATP source depleted. When mitochondrial protein import is impaired, a number of stress response pathways are activated in order to overcome the dysfunction and restore mitochondrial and cellular proteostasis. However, prolonged impaired mitochondrial protein import and subsequent defective respiratory chain function contributes to a number of diseases including primary mitochondrial diseases and neurodegeneration. This review focuses on how the processes of mitochondrial protein translocation and respiratory complex assembly and function are interlinked, how they are regulated, and their importance in health and disease.

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Mechanism of membrane-tethered mitochondrial protein synthesis

Cited by 86 publications

References 61 publications

Stepwise maturation of the peptidyl transferase region of human mitoribosomes

Stepwise maturation of the peptidyl transferase region of human mitoribosomes

Balanced mitochondrial and cytosolic translatomes underlie the biogenesis of human respiratory complexes

Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration

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