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Frontiers in Genetics 2018Ribosomes have been long considered as executors of the translational program. The fact that ribosomes can control the translation of specific mRNAs or entire cellular... (Review)
Review
Ribosomes have been long considered as executors of the translational program. The fact that ribosomes can control the translation of specific mRNAs or entire cellular programs is often neglected. Ribosomopathies, inherited diseases with mutations in ribosomal factors, show tissue specific defects and cancer predisposition. Studies of ribosomopathies have paved the way to the concept that ribosomes may control translation of specific mRNAs. Studies in and mice support the existence of heterogeneous ribosomes that differentially translate mRNAs to coordinate cellular programs. Recent studies have now shown that ribosomal activity is not only a critical regulator of growth but also of metabolism. For instance, glycolysis and mitochondrial function have been found to be affected by ribosomal availability. Also, ATP levels drop in models of ribosomopathies. We discuss findings highlighting the relevance of ribosome heterogeneity in physiological and pathological conditions, as well as the possibility that in rate-limiting situations, ribosomes may favor some translational programs. We discuss the effects of ribosome heterogeneity on cellular metabolism, tumorigenesis and aging. We speculate a scenario in which ribosomes are not only executors of a metabolic program but act as modulators.
PubMed: 30498507
DOI: 10.3389/fgene.2018.00533 -
Molecular & Cellular Proteomics : MCP Apr 2024Huntington disease (HD) is caused by an expanded polyglutamine mutation in huntingtin (mHTT) that promotes prominent atrophy in the striatum and subsequent psychiatric,...
Huntington disease (HD) is caused by an expanded polyglutamine mutation in huntingtin (mHTT) that promotes prominent atrophy in the striatum and subsequent psychiatric, cognitive deficits, and choreiform movements. Multiple lines of evidence point to an association between HD and aberrant striatal mitochondrial functions; however, the present knowledge about whether (or how) mitochondrial mRNA translation is differentially regulated in HD remains unclear. We found that protein synthesis is diminished in HD mitochondria compared to healthy control striatal cell models. We utilized ribosome profiling (Ribo-Seq) to analyze detailed snapshots of ribosome occupancy of the mitochondrial mRNA transcripts in control and HD striatal cell models. The Ribo-Seq data revealed almost unaltered ribosome occupancy on the nuclear-encoded mitochondrial transcripts involved in oxidative phosphorylation (SDHA, Ndufv1, Timm23, Tomm5, Mrps22) in HD cells. By contrast, ribosome occupancy was dramatically increased for mitochondrially encoded oxidative phosphorylation mRNAs (mt-Nd1, mt-Nd2, mt-Nd4, mt-Nd4l, mt-Nd5, mt-Nd6, mt-Co1, mt-Cytb, and mt-ATP8). We also applied tandem mass tag-based mass spectrometry identification of mitochondrial proteins to derive correlations between ribosome occupancy and actual mature mitochondrial protein products. We found many mitochondrial transcripts with comparable or higher ribosome occupancy, but diminished mitochondrial protein products, in HD. Thus, our study provides the first evidence of a widespread dichotomous effect on ribosome occupancy and protein abundance of mitochondria-related genes in HD.
Topics: Huntington Disease; Mitochondria; Humans; Protein Biosynthesis; Ribosomes; RNA, Messenger; Oxidative Phosphorylation; Corpus Striatum; Mitochondrial Proteins; Cell Line; RNA, Mitochondrial; Mass Spectrometry; Ribosome Profiling
PubMed: 38447791
DOI: 10.1016/j.mcpro.2024.100746 -
Molecular Cell Oct 2021To survive, mammalian cells must adapt to environmental challenges. While the cellular response to mild stress has been widely studied, how cells respond to severe...
To survive, mammalian cells must adapt to environmental challenges. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe hyperosmotic stress, cells enter a transient hibernation-like state in anticipation of recovery. We demonstrate this adaptive pausing response (APR) is a coordinated cellular response that limits ATP supply and consumption through mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery. We further show that recovery from severe stress involves ISR (integrated stress response) signaling that permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress via a hibernation-like mechanism that preserves vital elements of cellular function under harsh environmental conditions.
Topics: Adaptation, Physiological; Adenosine Triphosphate; Animals; Cell Proliferation; Codon, Initiator; Fibroblasts; HEK293 Cells; Humans; Kinetics; Mice; Mitochondria; Mitochondrial Proteins; Osmotic Pressure; Protein Biosynthesis; Ribosomes; Signal Transduction
PubMed: 34686314
DOI: 10.1016/j.molcel.2021.09.029 -
Trends in Biochemical Sciences Aug 2017Perturbation of mitochondrial DNA (mtDNA) gene expression can lead to human pathologies. Therefore, a greater appreciation of the basic mechanisms of mitochondrial gene... (Review)
Review
Perturbation of mitochondrial DNA (mtDNA) gene expression can lead to human pathologies. Therefore, a greater appreciation of the basic mechanisms of mitochondrial gene expression is desirable to understand the pathophysiology of associated disorders. Although the purpose of the mitochondrial gene expression machinery is to provide only 13 proteins of the oxidative phosphorylation (OxPhos) system, recent studies have revealed its remarkable and unexpected complexity. We review here the latest breakthroughs in our understanding of the post-transcriptional processes of mitochondrial gene expression, focusing on advances in analyzing the mitochondrial epitranscriptome, the role of mitochondrial RNA granules (MRGs), the benefits of recently obtained structures of the mitochondrial ribosome, and the coordination of mitochondrial and cytosolic translation to orchestrate the biogenesis of OxPhos complexes.
Topics: Animals; Gene Expression Regulation; Genes, Mitochondrial; Humans; Mitochondria; Mitochondrial Ribosomes; Oxidative Phosphorylation; RNA Processing, Post-Transcriptional
PubMed: 28285835
DOI: 10.1016/j.tibs.2017.02.003 -
International Journal of Molecular... Nov 2020Mammalian mitochondrial ribosomes translate 13 proteins encoded by mitochondrial genes, all of which play roles in the mitochondrial respiratory chain. After a long... (Review)
Review
Mammalian mitochondrial ribosomes translate 13 proteins encoded by mitochondrial genes, all of which play roles in the mitochondrial respiratory chain. After a long period of reconstruction, mitochondrial ribosomes are the most protein-rich ribosomes. Mitochondrial ribosomal proteins (MRPs) are encoded by nuclear genes, synthesized in the cytoplasm and then, transported to the mitochondria to be assembled into mitochondrial ribosomes. MRPs not only play a role in mitochondrial oxidative phosphorylation (OXPHOS). Moreover, they participate in the regulation of cell state as apoptosis inducing factors. Abnormal expressions of MRPs will lead to mitochondrial metabolism disorder, cell dysfunction, etc. Many researches have demonstrated the abnormal expression of MRPs in various tumors. This paper reviews the basic structure of mitochondrial ribosome, focuses on the structure and function of MRPs, and their relationships with cell apoptosis and diseases. It provides a reference for the study of the function of MRPs and the disease diagnosis and treatment.
Topics: Apoptosis; Gene Expression Regulation; Humans; Mitochondria; Mitochondrial Proteins; Mitochondrial Ribosomes; Neoplasms; Oxidative Phosphorylation; Ribosomal Proteins
PubMed: 33238645
DOI: 10.3390/ijms21228879 -
The Journal of Biological Chemistry Feb 2023Mitochondrial ribosomes are specialized to translate the 13 membrane proteins encoded in the mitochondrial genome, which shapes the oxidative phosphorylation complexes...
Mitochondrial ribosomes are specialized to translate the 13 membrane proteins encoded in the mitochondrial genome, which shapes the oxidative phosphorylation complexes essential for cellular energy metabolism. Despite the importance of mitochondrial translation (MT) control, it is challenging to identify and quantify the mitochondrial-encoded proteins because of their hydrophobic nature and low abundance. Here, we introduce a mass spectrometry-based proteomic method that combines biochemical isolation of mitochondria with pulse stable isotope labeling by amino acids in cell culture. Our method provides the highest protein identification rate with the shortest measurement time among currently available methods, enabling us to quantify 12 of the 13 mitochondrial-encoded proteins. We applied this method to uncover the global picture of (post-)translational regulation of both mitochondrial- and nuclear-encoded subunits of oxidative phosphorylation complexes. We found that inhibition of MT led to degradation of orphan nuclear-encoded subunits that are considered to form subcomplexes with the mitochondrial-encoded subunits. This method should be readily applicable to study MT programs in many contexts, including oxidative stress and mitochondrial disease.
Topics: Mitochondria; Mitochondrial Proteins; Mitochondrial Ribosomes; Oxidative Phosphorylation; Protein Biosynthesis; Proteomics
PubMed: 36603763
DOI: 10.1016/j.jbc.2022.102865 -
RNA Biology Feb 2020ATP is generated in mitochondria of eukaryotic cells by oxidative phosphorylation (OXPHOS). The OXPHOS complex, which is crucial for cellular metabolism, comprises of... (Review)
Review
ATP is generated in mitochondria of eukaryotic cells by oxidative phosphorylation (OXPHOS). The OXPHOS complex, which is crucial for cellular metabolism, comprises of both nuclear and mitochondrially encoded subunits. Also, the occurrence of several pathologies because of mutations in the mitochondrial translation apparatus indicates the importance of mitochondrial translation and its regulation. The mitochondrial translation apparatus is similar to its prokaryotic counterpart due to a common origin of evolution. However, mitochondrial translation has diverged from prokaryotic translation in many ways by reductive evolution. In this review, we focus on mammalian mitochondrial translation initiation, a highly regulated step of translation, and present a comparison with prokaryotic translation.
Topics: Animals; Disease Susceptibility; Humans; Mammals; Mitochondria; Mitochondrial Diseases; Mitochondrial Ribosomes; Models, Molecular; Peptide Chain Initiation, Translational; Prokaryotic Cells; Protein Biosynthesis; RNA, Messenger; RNA, Transfer; Ribosomes; Structure-Activity Relationship
PubMed: 31696767
DOI: 10.1080/15476286.2019.1690099 -
Trends in Parasitology Apr 2020The mitochondrion in parasitic protozoans is a clinically proven drug target. A specialized ribosome (mitoribosome) is required to translate genes encoded on the... (Review)
Review
The mitochondrion in parasitic protozoans is a clinically proven drug target. A specialized ribosome (mitoribosome) is required to translate genes encoded on the mitochondrial (mt) DNA. Despite the significance, little is known about mitoribosomes in many medically and economically important unicellular protozoans.
Topics: Animals; Eukaryota; Genetic Variation; Genome, Mitochondrial; Genome, Protozoan; Mitochondrial Ribosomes; Parasites
PubMed: 32191848
DOI: 10.1016/j.pt.2020.01.002 -
Cells Dec 2019Contrary to the widely held belief that mitochondrial ribosomes (mitoribosomes) are highly similar to bacterial ones, recent experimental evidence reveals that... (Review)
Review
Contrary to the widely held belief that mitochondrial ribosomes (mitoribosomes) are highly similar to bacterial ones, recent experimental evidence reveals that mitoribosomes do differ significantly from their bacterial counterparts. This review is focused on plant mitoribosomes, but we also highlight the most striking similarities and differences between the plant and non-plant mitoribosomes. An analysis of the composition and structure of mitoribosomes in trypanosomes, yeast, mammals and plants uncovers numerous organism-specific features. For the plant mitoribosome, the most striking feature is the enormous size of the small subunit compared to the large one. Apart from the new structural information, possible functional peculiarities of different types of mitoribosomes are also discussed. Studies suggest that the protein composition of mitoribosomes is dynamic, especially during development, giving rise to a heterogeneous populations of ribosomes fulfilling specific functions. Moreover, convincing data shows that mitoribosomes interact with components involved in diverse mitochondrial gene expression steps, forming large expressosome-like structures.
Topics: Genetic Variation; Humans; Mitochondria; Mitochondrial Membranes; Mitochondrial Ribosomes; Plants; RNA, Ribosomal; Ribosomal Proteins
PubMed: 31816993
DOI: 10.3390/cells8121562 -
The Journal of Biological Chemistry Jul 2021Pentatricopeptide repeat (PPR) proteins are a large family of proteins that act primarily at different posttranscriptional steps of organellar gene expression. We have...
Pentatricopeptide repeat (PPR) proteins are a large family of proteins that act primarily at different posttranscriptional steps of organellar gene expression. We have previously found that the Schizosaccharomyces pombe PPR protein mpal10 interacts with mitochondrial translational activator Mpa1, and both are essential for mitochondrial protein synthesis. However, it is unclear how these two proteins function in mitochondrial protein synthesis in S. pombe. In this study, we further investigated the role of Ppr10 and Mpa1 in mitochondrial protein synthesis. Mitochondrial translational initiation requires two initiation factors, Mti2 and Mti3, which bind to the small subunit of the mitochondrial ribosome (mt-SSU) during the formation of the mitochondrial translational initiation complex. Using sucrose gradient sedimentation analysis, we found that disruption of ppr10, mpa1, or the PPR motifs in Ppr10 impairs the association of Mti2 and Mti3 with the mt-SSU, suggesting that both Ppr10 and Mpa1 may be required for the interaction of Mti2 and Mti3 with the mt-SSU during the assembly of mitochondrial translational initiation complex. Loss of Ppr10 perturbs the association of mitochondrially encoded cytochrome b (cob1) and cytochrome c oxidase subunit 1 (cox1) mRNAs with assembled mitochondrial ribosomes. Proteomic analysis revealed that a fraction of Ppr10 and Mpa1 copurified with a subset of mitoribosomal proteins. The PPR motifs of Ppr10 are necessary for its interaction with Mpa1 and that disruption of these PPR motifs impairs mitochondrial protein synthesis. Our results suggest that Ppr10 and Mpa1 function together to mediate mitochondrial translational initiation.
Topics: Binding Sites; Carrier Proteins; Eukaryotic Initiation Factors; Mitochondria; Mitochondrial Proteins; Mitochondrial Ribosomes; Peptide Chain Initiation, Translational; Protein Binding; RNA, Messenger; RNA-Binding Proteins; Schizosaccharomyces; Schizosaccharomyces pombe Proteins
PubMed: 34119521
DOI: 10.1016/j.jbc.2021.100869