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International Journal of Molecular... Jan 2022The eukaryotic translation initiation factor 5A (eIF5A) is an evolutionarily conserved protein that binds ribosomes to facilitate the translation of peptide motifs with... (Review)
Review
The eukaryotic translation initiation factor 5A (eIF5A) is an evolutionarily conserved protein that binds ribosomes to facilitate the translation of peptide motifs with consecutive prolines or combinations of prolines with glycine and charged amino acids. It has also been linked to other molecular functions and cellular processes, such as nuclear mRNA export and mRNA decay, proliferation, differentiation, autophagy, and apoptosis. The growing interest in eIF5A relates to its association with the pathogenesis of several diseases, including cancer, viral infection, and diabetes. It has also been proposed as an anti-aging factor: its levels decay in aged cells, whereas increasing levels of active eIF5A result in the rejuvenation of the immune and vascular systems and improved brain cognition. Recent data have linked the role of eIF5A in some pathologies with its function in maintaining healthy mitochondria. The eukaryotic translation initiation factor 5A is upregulated under respiratory metabolism and its deficiency reduces oxygen consumption, ATP production, and the levels of several mitochondrial metabolic enzymes, as well as altering mitochondria dynamics. However, although all the accumulated data strongly link eIF5A to mitochondrial function, the precise molecular role and mechanisms involved are still unknown. In this review, we discuss the findings linking eIF5A and mitochondria, speculate about its role in regulating mitochondrial homeostasis, and highlight its potential as a target in diseases related to energy metabolism.
Topics: Energy Metabolism; Humans; Mitochondria; Peptide Initiation Factors; Peptides; RNA-Binding Proteins; Ribosomes; Eukaryotic Translation Initiation Factor 5A
PubMed: 35163207
DOI: 10.3390/ijms23031284 -
Methods in Molecular Biology (Clifton,... 2023Mitochondrial protein synthesis is essential for the life of aerobic eukaryotes. Without it, oxidative phosphorylation cannot be coupled. Evolution has shaped a battery...
Mitochondrial protein synthesis is essential for the life of aerobic eukaryotes. Without it, oxidative phosphorylation cannot be coupled. Evolution has shaped a battery of factors and machinery that are key to production of just a handful of critical proteins. In this general concept chapter, we attempt to briefly summarize our current knowledge of the overall process in mitochondria from a variety of species, breaking this down to the four parts of translation: initiation, elongation, termination, and recycling. Where appropriate, we highlight differences between species and emphasize gaps in our understanding. Excitingly, with the current revolution in cryoelectron microscopy and mitochondrial genome editing, it is highly likely that many of these gaps will be resolved in the near future. However, the absence of a faithful in vitro reconstituted system to study mitochondrial translation is still problematic.
Topics: Mitochondrial Ribosomes; Cryoelectron Microscopy; Mitochondria; Protein Biosynthesis; Oxidative Phosphorylation; Mitochondrial Proteins
PubMed: 37166631
DOI: 10.1007/978-1-0716-3171-3_4 -
RNA Biology 2022The universally conserved process of protein biosynthesis is crucial for maintaining cellular homoeostasis and in eukaryotes, mitochondrial translation is essential for... (Review)
Review
The universally conserved process of protein biosynthesis is crucial for maintaining cellular homoeostasis and in eukaryotes, mitochondrial translation is essential for aerobic energy production. Mitochondrial ribosomes (mitoribosomes) are highly specialized to synthesize 13 core subunits of the oxidative phosphorylation (OXPHOS) complexes. Although the mitochondrial translation machinery traces its origin from a bacterial ancestor, it has acquired substantial differences within this endosymbiotic environment. The cycle of mitoribosome function proceeds through the conserved canonical steps of initiation, elongation, termination and mitoribosome recycling. However, when mitoribosomes operate in the context of limited translation factors or on aberrant mRNAs, they can become stalled and activation of rescue mechanisms is required. This review summarizes recent advances in the understanding of protein biosynthesis in mitochondria, focusing especially on the mechanistic and physiological details of translation termination, and mitoribosome recycling and rescue.
Topics: Animals; Bacteria; Eukaryota; Humans; Mitochondria; Mitochondrial Proteins; Mitochondrial Ribosomes; Protein Biosynthesis
PubMed: 34923906
DOI: 10.1080/15476286.2021.2015561 -
Trends in Biochemical Sciences Jul 2023The mitochondrial ribosome (mitoribosome) is a multicomponent machine that has unique structural features. Biogenesis of the human mitoribosome includes correct... (Review)
Review
The mitochondrial ribosome (mitoribosome) is a multicomponent machine that has unique structural features. Biogenesis of the human mitoribosome includes correct maturation and folding of the mitochondria-encoded RNA components (12S and 16S mt-rRNAs, and mt-tRNAVal) and their assembly together with 82 nucleus-encoded mitoribosomal proteins. This complex process requires the coordinated action of multiple assembly factors. Recent advances in single-particle cryo-electron microscopy (cryo-EM) have provided detailed insights into the specific functions of several mitoribosome assembly factors and have defined their timing. In this review we summarize mitoribosomal small (mtSSU) and large subunit (mtLSU) biogenesis based on structural findings, and we discuss potential crosstalk between mtSSU and mtLSU assembly pathways as well as coordination between mitoribosome biogenesis and other processes involved in mitochondrial gene expression.
Topics: Humans; Cryoelectron Microscopy; Mitochondrial Ribosomes; RNA, Ribosomal, 16S; Mitochondrial Proteins; Ribosomal Proteins
PubMed: 37169615
DOI: 10.1016/j.tibs.2023.04.002 -
Trends in Cell Biology Apr 2020Maintaining cellular protein homeostasis (proteostasis) is an essential task for all eukaryotes. Proteostasis failure worsens with aging and is considered a cause of and... (Review)
Review
Maintaining cellular protein homeostasis (proteostasis) is an essential task for all eukaryotes. Proteostasis failure worsens with aging and is considered a cause of and a therapeutic target for age-related diseases including neurodegenerative disorders. The cellular networks regulating proteostasis and the pathogenic events driving proteostasis failure in disease remain poorly understood. Model organism studies in yeast and Drosophila reveal an intriguing link between mitochondrial function and proteostasis. In this review we examine recent findings on mitochondrial outer membrane (MOM)-associated mRNA translation, how this process is sensitive to mitochondrial dysfunction and constantly surveyed by ribosome-associated quality control (RQC), and how defects in this process generate aberrant proteins with unusual C-terminal extensions (CTEs) that promote aggregation and drive proteostasis failure. We also discuss the implications for human diseases.
Topics: Animals; Cytosol; Humans; Mitochondria; Mitochondrial Membranes; Models, Biological; Proteostasis; Ribosomes
PubMed: 32200806
DOI: 10.1016/j.tcb.2020.01.008 -
Frontiers in Physiology 2021Skeletal muscle adaptations to resistance and endurance training include increased ribosome and mitochondrial biogenesis, respectively. Such adaptations are believed to... (Review)
Review
Skeletal muscle adaptations to resistance and endurance training include increased ribosome and mitochondrial biogenesis, respectively. Such adaptations are believed to contribute to the notable increases in hypertrophy and aerobic capacity observed with each exercise mode. Data from multiple studies suggest the existence of a competition between ribosome and mitochondrial biogenesis, in which the first adaptation is prioritized with resistance training while the latter is prioritized with endurance training. In addition, reports have shown an interference effect when both exercise modes are performed concurrently. This prioritization/interference may be due to the interplay between the 5' AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) signaling cascades and/or the high skeletal muscle energy requirements for the synthesis and maintenance of cellular organelles. Negative associations between ribosomal DNA and mitochondrial DNA copy number in human blood cells also provide evidence of potential competition in skeletal muscle. However, several lines of evidence suggest that ribosome and mitochondrial biogenesis can occur simultaneously in response to different types of exercise and that the AMPK-mTORC1 interaction is more complex than initially thought. The purpose of this review is to provide in-depth discussions of these topics. We discuss whether a between mitochondrial and ribosome biogenesis exists and show the available evidence both in favor and against it. Finally, we provide future research avenues in this area of exercise physiology.
PubMed: 34646153
DOI: 10.3389/fphys.2021.725866 -
Molecular Cell Dec 2021Mitochondria contain a specific translation machinery for the synthesis of mitochondria-encoded respiratory chain components. Mitochondrial tRNAs (mt-tRNAs) are also...
Mitochondria contain a specific translation machinery for the synthesis of mitochondria-encoded respiratory chain components. Mitochondrial tRNAs (mt-tRNAs) are also generated from the mitochondrial DNA and, similar to their cytoplasmic counterparts, are post-transcriptionally modified. Here, we find that the RNA methyltransferase METTL8 is a mitochondrial protein that facilitates 3-methyl-cytidine (mC) methylation at position C of the mt-tRNA and mt-tRNA. METTL8 knockout cells show a reduction in respiratory chain activity, whereas overexpression increases activity. In pancreatic cancer, METTL8 levels are high, which correlates with lower patient survival and an enhanced respiratory chain activity. Mitochondrial ribosome profiling uncovered mitoribosome stalling on mt-tRNA- and mt-tRNA-dependent codons. Further analysis of the respiratory chain complexes using mass spectrometry revealed reduced incorporation of the mitochondrially encoded proteins ND6 and ND1 into complex I. The well-balanced translation of mt-tRNA- and mt-tRNA-dependent codons through METTL8-mediated mC methylation might, therefore, facilitate the optimal composition and function of the mitochondrial respiratory chain.
Topics: Animals; Anticodon; Cell Proliferation; Codon; Cytoplasm; DNA, Mitochondrial; Electron Transport; Green Fluorescent Proteins; HEK293 Cells; Humans; Methyltransferases; Mice; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Oxygen Consumption; Pancreatic Neoplasms; RNA, Mitochondrial; RNA, Transfer; Ribosomes; Up-Regulation
PubMed: 34774131
DOI: 10.1016/j.molcel.2021.10.018 -
The Journal of Physiology Jul 2021The evolutionary acquisition of mitochondria has given rise to the diversity of eukaryotic life. Mitochondria have retained their ancestral α-proteobacterial traits... (Review)
Review
The evolutionary acquisition of mitochondria has given rise to the diversity of eukaryotic life. Mitochondria have retained their ancestral α-proteobacterial traits through the maintenance of double membranes and their own circular genome. Their genome varies in size from very large in plants to the smallest in animals and their parasites. The mitochondrial genome encodes essential genes for protein synthesis and has to coordinate its expression with the nuclear genome from which it sources most of the proteins required for mitochondrial biogenesis and function. The mitochondrial protein synthesis machinery is unique because it is encoded by both the nuclear and mitochondrial genomes thereby requiring tight regulation to produce the respiratory complexes that drive oxidative phosphorylation for energy production. The fidelity and coordination of mitochondrial protein synthesis are essential for ATP production. Here we compare and contrast the mitochondrial translation mechanisms in mammals and fungi to bacteria and reveal that their diverse regulation can have unusual impacts on the health and disease of these organisms. We highlight that in mammals the rate of protein synthesis is more important than the fidelity of translation, enabling coordinated biogenesis of the mitochondrial respiratory chain with respiratory chain proteins synthesised by cytoplasmic ribosomes. Changes in mitochondrial protein fidelity can trigger the activation of the diverse cellular signalling networks in fungi and mammals to combat dysfunction in energy conservation. The physiological consequences of altered fidelity of protein synthesis can range from liver regeneration to the onset and development of cardiomyopathy.
Topics: Animals; Genome, Mitochondrial; Mitochondria; Mitochondrial Proteins; Protein Biosynthesis; Ribosomes
PubMed: 32710561
DOI: 10.1113/JP280359 -
Biochemistry. Biokhimiia Sep 2021When a ribosome encounters the stop codon of an mRNA, it terminates translation, releases the newly made protein, and is recycled to initiate translation on a new mRNA.... (Review)
Review
When a ribosome encounters the stop codon of an mRNA, it terminates translation, releases the newly made protein, and is recycled to initiate translation on a new mRNA. Termination is a highly dynamic process in which release factors (RF1 and RF2 in bacteria; eRF1•eRF3•GTP in eukaryotes) coordinate peptide release with large-scale molecular rearrangements of the ribosome. Ribosomes stalled on aberrant mRNAs are rescued and recycled by diverse bacterial, mitochondrial, or cytoplasmic quality control mechanisms. These are catalyzed by rescue factors with peptidyl-tRNA hydrolase activity (bacterial ArfA•RF2 and ArfB, mitochondrial ICT1 and mtRF-R, and cytoplasmic Vms1), that are distinct from each other and from release factors. Nevertheless, recent structural studies demonstrate a remarkable similarity between translation termination and ribosome rescue mechanisms. This review describes how these pathways rely on inherent ribosome dynamics, emphasizing the active role of the ribosome in all translation steps.
Topics: Bacteria; Bacterial Proteins; Carboxylic Ester Hydrolases; Cytoplasm; Mitochondria; Peptide Chain Termination, Translational; Protein Biosynthesis; RNA-Binding Proteins; Ribosomal Proteins; Ribosomes
PubMed: 34565314
DOI: 10.1134/S0006297921090066 -
Frontiers in Genetics 2020Ribosomal RNA (rRNA) from all organisms undergoes post-transcriptional modifications that increase the diversity of its composition and activity. In mitochondria,... (Review)
Review
Ribosomal RNA (rRNA) from all organisms undergoes post-transcriptional modifications that increase the diversity of its composition and activity. In mitochondria, specialized mitochondrial ribosomes (mitoribosomes) are responsible for the synthesis of 13 oxidative phosphorylation proteins encoded by the mitochondrial genome. Mitoribosomal RNA is also modified, with 10 modifications thus far identified and all corresponding modifying enzymes described. This form of epigenetic regulation of mitochondrial gene expression affects mitoribosome biogenesis and function. Here, we provide an overview on rRNA methylation and highlight critical work that is beginning to elucidate its role in mitochondrial gene expression. Given the similarities between bacterial and mitochondrial ribosomes, we focus on studies involving and human models. Furthermore, we highlight the use of state-of-the-art technologies, such as cryoEM in the study of rRNA methylation and its biological relevance. Understanding the mechanisms and functional relevance of this process represents an exciting frontier in the RNA biology and mitochondrial fields.
PubMed: 32765591
DOI: 10.3389/fgene.2020.00761