bims-mitran 2021-12-19 papers

bims-mitran

Biomed News

on Mitochondrial translation

Issue of 2021–12–19
six papers selected by
Andreas Kohler, Stockholm University

Dysfunctional mitochondrial translation and combined oxidative phosphorylation deficiency in a mouse model of hepatoencephalopathy due to Gfm1 mutations.
Time-resolved cryo-EM visualizes ribosomal translocation with EF-G and GTP.
The role of mitochondrial dynamics in mtDNA maintenance.
Combinations of slow-translating codon clusters can increase mRNA half-life in Saccharomyces cerevisiae.
Telomere Length but Not Mitochondrial DNA Copy Number Is Altered in Both Young and Old COPD.
Genetic landscape of human mitochondrial genome using whole genome sequencing.

FASEB J. 2022 Jan;36(1): e22091

Dysfunctional mitochondrial translation and combined oxidative phosphorylation deficiency in a mouse model of hepatoencephalopathy due to Gfm1 mutations.

Miguel Molina-Berenguer, Ferran Vila-Julià, Sandra Pérez-Ramos, Maria Teresa Salcedo-Allende, Yolanda Cámara, Javier Torres-Torronteras, Ramon Martí.

  Hepatoencephalopathy due to combined oxidative phosphorylation deficiency type 1 (COXPD1) is a recessive mitochondrial translation disorder caused by mutations in GFM1, a nuclear gene encoding mitochondrial elongation factor G1 (EFG1). Patients with COXPD1 typically present hepatoencephalopathy early after birth with rapid disease progression, and usually die within the first few weeks or years of life. We have generated two different mouse models: a Gfm1 knock-in (KI) harboring the p.R671C missense mutation, found in at least 10 patients who survived more than 1 year, and a Gfm1 knock-out (KO) model. Homozygous KO mice (Gfm1-/- ) were embryonically lethal, whereas homozygous KI (Gfm1R671C / R671C ) mice were viable and showed normal growth. R671C mutation in Gfm1 caused drastic reductions in the mitochondrial EFG1 protein content in different organs. Six- to eight-week-old Gfm1R671C / R671C mice showed partial reductions of in organello mitochondrial translation and respiratory complex IV enzyme activity in the liver. Compound heterozygous Gfm1R671C /- showed a more pronounced decrease of EFG1 protein in liver and brain mitochondria, as compared with Gfm1R671C / R671C mice. At 8 weeks of age, their mitochondrial translation rates were significantly reduced in both tissues. Additionally, Gfm1R671C /- mice showed combined oxidative phosphorylation deficiency (reduced complex I and IV enzyme activities in liver and brain), and blue native polyacrylamide gel electrophoresis analysis revealed lower amounts of both affected complexes. We conclude that the compound heterozygous Gfm1R671C /- mouse presents a clear dysfunctional molecular phenotype, showing impaired mitochondrial translation and combined respiratory chain dysfunction, making it a suitable animal model for the study of COXPD1.

Keywords:   Gfm1 ; COXPD1; animal model; elongation factor G1; mitochondria; translation

DOI:  https://doi.org/10.1096/fj.202100819RRR
Nat Commun. 2021 Dec 13. 12(1): 7236

Time-resolved cryo-EM visualizes ribosomal translocation with EF-G and GTP.

Christine E Carbone, Anna B Loveland, Howard B Gamper, Ya-Ming Hou, Gabriel Demo, Andrei A Korostelev.

During translation, a conserved GTPase elongation factor-EF-G in bacteria or eEF2 in eukaryotes-translocates tRNA and mRNA through the ribosome. EF-G has been proposed to act as a flexible motor that propels tRNA and mRNA movement, as a rigid pawl that biases unidirectional translocation resulting from ribosome rearrangements, or by various combinations of motor- and pawl-like mechanisms. Using time-resolved cryo-EM, we visualized GTP-catalyzed translocation without inhibitors, capturing elusive structures of ribosome•EF-G intermediates at near-atomic resolution. Prior to translocation, EF-G binds near peptidyl-tRNA, while the rotated 30S subunit stabilizes the EF-G GTPase center. Reverse 30S rotation releases Pi and translocates peptidyl-tRNA and EF-G by ~20 Å. An additional 4-Å translocation initiates EF-G dissociation from a transient ribosome state with highly swiveled 30S head. The structures visualize how nearly rigid EF-G rectifies inherent and spontaneous ribosomal dynamics into tRNA-mRNA translocation, whereas GTP hydrolysis and Pi release drive EF-G dissociation.

DOI: https://doi.org/10.1038/s41467-021-27415-0
J Cell Sci. 2021 Dec 15. pii: jcs258944. [Epub ahead of print]134(24):

The role of mitochondrial dynamics in mtDNA maintenance.

Rasha Sabouny, Timothy E Shutt.

  The dynamic nature of mitochondria, which can fuse, divide and move throughout the cell, allows these critical organelles to adapt their function in response to cellular demands, and is also important for regulating mitochondrial DNA (mtDNA). While it is established that impairments in mitochondrial fusion and fission impact the mitochondrial genome and can lead to mtDNA depletion, abnormal nucleoid organization or accumulation of deletions, it is not entirely clear how or why remodeling mitochondrial network morphology affects mtDNA. Here, we focus on recent advances in our understanding of how mitochondrial dynamics contribute to the regulation of mtDNA and discuss links to human disease.

Keywords:  Fission; Fusion; Mitochondria; Mitochondrial dynamics; Mitophagy; mtDNA

DOI:  https://doi.org/10.1242/jcs.258944
Proc Natl Acad Sci U S A. 2021 Dec 21. pii: e2026362118. [Epub ahead of print]118(51):

Combinations of slow-translating codon clusters can increase mRNA half-life in Saccharomyces cerevisiae.

Ajeet K Sharma, Johannes Venezian, Ayala Shiber, Günter Kramer, Bernd Bukau, Edward P O'Brien.

  The presence of a single cluster of nonoptimal codons was found to decrease a transcript's half-life through the interaction of the ribosome-associated quality control machinery with stalled ribosomes in Saccharomyces cerevisiae The impact of multiple nonoptimal codon clusters on a transcript's half-life, however, is unknown. Using a kinetic model, we predict that inserting a second nonoptimal cluster near the 5' end can lead to synergistic effects that increase a messenger RNA's (mRNA's) half-life in S. cerevisiae Specifically, the 5' end cluster suppresses the formation of ribosome queues, reducing the interaction of ribosome-associated quality control factors with stalled ribosomes. We experimentally validate this prediction by introducing two nonoptimal clusters into three different genes and find that their mRNA half-life increases up to fourfold. The model also predicts that in the presence of two clusters, the cluster closest to the 5' end is the primary determinant of mRNA half-life. These results suggest the "translational ramp," in which nonoptimal codons are located near the start codon and increase translational efficiency, may have the additional biological benefit of allowing downstream slow-codon clusters to be present without decreasing mRNA half-life. These results indicate that codon usage bias plays a more nuanced role in controlling cellular protein levels than previously thought.

Keywords:  mRNA half-life; ribosome collisions; synonymous codons

DOI:  https://doi.org/10.1073/pnas.2026362118
Front Med (Lausanne). 2021 ;8 761767

Telomere Length but Not Mitochondrial DNA Copy Number Is Altered in Both Young and Old COPD.

Sandra Casas-Recasens, Nuria Mendoza, Alejandra López-Giraldo, Tamara Garcia, Borja G Cosio, Sergi Pascual-Guardia, Ady Acosta-Castro, Alicia Borras-Santos, Joaquim Gea, Gloria Garrabou, Alvar Agusti, Rosa Faner.

  Accelerated ageing is implicated in the pathogenesis of respiratory diseases as chronic obstructive pulmonary disease (COPD), but recent evidence indicates that the COPD can have roots early in life. Here we hypothesise that the accelerated ageing markers might have a role in the pathobiology of young COPD. The objective of this study was to compare two hallmarks of ageing, telomere length (TL), and mitochondrial DNA copy number (mtDNA-CN, as a surrogate marker of mitochondrial dysfunction) in young (≤ 50 years) and old (>50 years) smokers, with and without COPD. Both, TL and mtDNA-CN were measured in whole blood DNA by quantitative PCR [qPCR] in: (1) young ever smokers with (n = 81) or without (n = 166) COPD; and (2) old ever smokers with (n = 159) or without (n = 29) COPD. A multivariable linear regression was used to assess the association of TL and mtDNA-CN with lung function. We observed that in the entire study population, TL and mtDNA-CN decreased with age, and the former but not the latter related to FEV1/FVC (%), FEV1 (% ref.), and DLCO (% ref.). The short telomeres were found both in the young and old patients with severe COPD (FEV1 <50% ref.). In addition, we found that TL and mtDNA-CN were significantly correlated, but their relationship was positive in younger while negative in the older patients with COPD, suggesting a mitochondrial dysfunction. We conclude that TL, but not mtDNA-CN, is associated with the lung function impairment. Both young and old patients with severe COPD have evidence of accelerated ageing (shorter TL) but differ in the direction of the correlation between TL and mtDNA-CN in relation to age.

Keywords:  ageing; chronic bronchitis; emphysema; mitochondrial DNA; telomeres

DOI:  https://doi.org/10.3389/fmed.2021.761767
Hum Mol Genet. 2021 Dec 13. pii: ddab358. [Epub ahead of print]

Genetic landscape of human mitochondrial genome using whole genome sequencing.

Yijing Wang, Guihu Zhao, Zhenghuan Fang, Hongxu Pan, Yuwen Zhao, Yige Wang, Xun Zhou, Xiaomeng Wang, Tengfei Luo, Yi Zhang, Zheng Wang, Qian Chen, Lijie Dong, Yuanfeng Huang, Qiao Zhou, Lu Xia, Bin Li, Jifeng Guo, Kun Xia, Beisha Tang, Jinchen Li.

Increasing evidences suggest that mitochondrial dysfunction is implicated in diseases and aging, and whole-genome sequencing (WGS) is the most unbiased method in analyzing the mitochondrial genome (mtDNA). However, the genetic landscape of mtDNA in the Chinese population has not been fully examined. Here, we described the genetic landscape of mtDNA using WGS data from Chinese individuals (n = 3241). We identified 3892 mtDNA variants, of which 3349 (86%) were rare variants. Interestingly, we observed a trend toward extreme heterogeneity of mtDNA variants. Our study observed a distinct purifying selection on mtDNA, which inhibits the accumulation of harmful heteroplasmies at the individual level: (1) mitochondrial dN/dS ratios were much less than 1; (2) the dN/dS ratio of heteroplasmies was higher than homoplasmies; (3) heteroplasmies had more indels and predicted deleterious variants than homoplasmies. Furthermore, we found that haplogroup M (20.27%) and D (20.15%) had the highest frequencies in the Chinese population, followed by B (18.51%) and F (16.45%). The number of variants per individual differed across haplogroup groups, with a higher number of homoplasmies for the M lineage. Meanwhile, mtDNA copy number was negatively correlated with age but positively correlated with the female sex. Finally, we developed an mtDNA variation database of Chinese populations called MTCards (http://genemed.tech/mtcards/) to facilitate the query of mtDNA variants in this study. In summary, these findings contribute to different aspects of understanding mtDNA, providing a better understanding of the genetic basis of mitochondrial-related diseases.

DOI: https://doi.org/10.1093/hmg/ddab358