Stepwise maturation of the peptidyl transferase region of human mitoribosomes

Lenarčič, Tea; Jaskółowski, Mateusz; Leibundgut, Marc; Scaiola, Alain; Schönhut, Tanja; Saurer, Martin; Lee, Richard G.; Rackham, Oliver; Filipovska, Aleksandra; Ban, Nenad

doi:10.1038/s41467-021-23811-8

Cited by 33 publications

(29 citation statements)

References 54 publications

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“…A comprehensive review of GTPases in human mitoribosomal assembly ( Maiti et al, 2021 ) and four studies describing cryo-EM structures of mtLSU late assembly intermediates distinct from ours and from each other ( Cheng et al, 2021 ; Cipullo et al, 2021 ; Hillen et al, 2021 ; Lenarčič et al, 2021 ), appeared during manuscript preparation. All five studies, including ours, have trapped MALSU1·L0R8F8·mt-ACP and NSUN4·MTERF4 at the same location on the mtLSU.…”

Section: Discussionmentioning

confidence: 99%

Visualizing formation of the active site in the mitochondrial ribosome

Chandrasekaran

Desai

Burton

et al. 2021

eLife

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Ribosome assembly is an essential and conserved process that is regulated at each step by specific factors. Using cryo-electron microscopy (cryo-EM), we visualize the formation of the conserved peptidyl transferase center (PTC) of the human mitochondrial ribosome. The conserved GTPase GTPBP7 regulates the correct folding of 16S ribosomal RNA (rRNA) helices and ensures 2ʹ-O-methylation of the PTC base U3039. GTPBP7 binds the RNA methyltransferase NSUN4 and MTERF4, which sequester H68-71 of the 16S rRNA and allow biogenesis factors to access the maturing PTC. Mutations that disrupt binding of their Caenorhabditis elegans orthologs to the large subunit potently activate mitochondrial stress and cause viability, development, and sterility defects. Next-generation RNA sequencing reveals widespread gene expression changes in these mutant animals that are indicative of mitochondrial stress response activation. We also answer the long-standing question of why NSUN4, but not its enzymatic activity, is indispensable for mitochondrial protein synthesis.

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Section: Discussionmentioning

confidence: 99%

Visualizing formation of the active site in the mitochondrial ribosome

Chandrasekaran

Desai

Burton

et al. 2021

eLife

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“…S2a). To define the role of p17/PERMIT-ICT1 association in CerS1's mitochondrial trafficking, we generated a mutant of p17/PERMIT with the conversion of Phe-Leu-Arg-Asn (residues [39][40][41][42] to Ala. These residues are predicted to be involved in ribosome binding (RB) based on the homology of ribosomal L1 protein's 23S rRNA recognition motif (Suppl.…”

Section: Resultsmentioning

confidence: 99%

“…Mitochondrial ribosomes (mitoribosomes) are specialized to translate mitochondrial genes that encode protein subunits involved in oxidative phosphorylation [36][37][38][39] . The mitoribosome subunits require a multistep maturation process involving GTP-binding proteins (GTPBPs), which provide energy through GTP hydrolysis's assembly stages 40 . Mitoribosome defects were associated with poor clinical outcomes in patients with hepatocellular carcinoma immune suppression and evasion.…”

Section: Discussionmentioning

confidence: 99%

Alterations of Lipid-Mediated Mitophagy Result in Aging-Dependent Sensorimotor Defects

Natalia

Albayram

Kassir

et al. 2022

Preprint

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The metabolic consequences of mitophagy alterations due to age-related stress in healthy aging brains vs. neurodegeneration remain unknown. Here, we demonstrate that ceramide synthase 1 (CerS1) is transported to the outer mitochondrial membrane (OMM) by the p17/PERMIT transporter that recognizes mislocalized mitochondrial ribosomes (mitoribosomes) via 39-FLRN-42 residues, inducing ceramide-mediated mitophagy. P17/PERMIT-CerS1-mediated mitophagy attenuated the argininosuccinate/fumarate/malate axis and induced D-glucose and fructose accumulation in neurons in culture, and brain tissues (primarily in the cerebellum) of wild-type mice in vivo. These metabolic changes in response to sodium-selenite were nullified in the cerebellum of CerS1top/top, PARKIN-/- or p17/PERMIT-/- mice that have dysfunctional mitophagy. Whereas sodium selenite induced mitophagy in the cerebellum, and improved motor-neuron deficits in aged wild-type mice, exogenous fumarate or malate prevented mitophagy. Attenuation of ceramide-mediated mitophagy enhanced damaged mitochondria accumulation and age-dependent sensorimotor abnormalities in p17/PERMIT-/- mice. Reinstituting mitophagy using a ceramide analog drug with selenium conjugate, LCL768, restored mitophagy and reduced malate/fumarate metabolism, improving sensorimotor deficits in old p17/PERMIT-/- mice. Thus, these data describe metabolic consequences of alterations to P17/PERMIT/ceramide-mediated mitophagy associated with the loss of mitochondrial quality control in the brain and provide therapeutic options to overcome age-dependent sensorimotor deficits and related disorders like amyotrophic lateral sclerosis (ALS).

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“…This is also the case for all the maturation factors involved in mitoribosome biogenesis. Recently, several studies managed to capture mitoribosome assembly intermediates from humans [ 127 , 128 , 129 , 130 , 131 ] and kinetoplastids [ 95 , 98 , 99 , 132 , 133 ], describing different steps and factors involved in the maturation of the large and small mitoribosomal subunits. A portion of these factors were previously described by non-structural means [ 59 , 134 , 135 , 136 ], but most of them were described for the first time with these studies, and most importantly, directly observed in action.…”

Section: Functions and Modes Of Action Of Mitoribosome-specific Proteinsmentioning

confidence: 99%

Types and Functions of Mitoribosome-Specific Ribosomal Proteins across Eukaryotes

Scaltsoyiannes

Corre

Waltz

et al. 2022

IJMS

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Mitochondria are key organelles that combine features inherited from their bacterial endosymbiotic ancestor with traits that arose during eukaryote evolution. These energy producing organelles have retained a genome and fully functional gene expression machineries including specific ribosomes. Recent advances in cryo-electron microscopy have enabled the characterization of a fast-growing number of the low abundant membrane-bound mitochondrial ribosomes. Surprisingly, mitoribosomes were found to be extremely diverse both in terms of structure and composition. Still, all of them drastically increased their number of ribosomal proteins. Interestingly, among the more than 130 novel ribosomal proteins identified to date in mitochondria, most of them are composed of a-helices. Many of them belong to the nuclear encoded super family of helical repeat proteins. Here we review the diversity of functions and the mode of action held by the novel mitoribosome proteins and discuss why these proteins that share similar helical folds were independently recruited by mitoribosomes during evolution in independent eukaryote clades.

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Stepwise maturation of the peptidyl transferase region of human mitoribosomes

Cited by 33 publications

References 54 publications

Visualizing formation of the active site in the mitochondrial ribosome

Visualizing formation of the active site in the mitochondrial ribosome

Alterations of Lipid-Mediated Mitophagy Result in Aging-Dependent Sensorimotor Defects

Types and Functions of Mitoribosome-Specific Ribosomal Proteins across Eukaryotes

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