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Cells Sep 2020Modified nucleotides are present in all ribosomal RNA molecules. Mitochondrial ribosomes are unique to have a set of methylated residues that includes universally... (Review)
Review
Modified nucleotides are present in all ribosomal RNA molecules. Mitochondrial ribosomes are unique to have a set of methylated residues that includes universally conserved ones, those that could be found either in bacterial or in archaeal/eukaryotic cytosolic ribosomes and those that are present exclusively in mitochondria. A single pseudouridine within the mt-rRNA is located in the peptidyltransferase center at a position similar to that in bacteria. After recent completion of the list of enzymes responsible for the modification of mammalian mitochondrial rRNA it became possible to summarize an evolutionary history, functional role of mt-rRNA modification enzymes and an interplay of the mt-rRNA modification and mitoribosome assembly process, which is a goal of this review.
Topics: Animals; Evolution, Molecular; Humans; Mammals; Mitochondria; Peptidyl Transferases; Pseudouridine; RNA, Mitochondrial; RNA, Ribosomal; Ribosomes
PubMed: 32992603
DOI: 10.3390/cells9102181 -
IScience Sep 2022The human brain consumes five orders of magnitude more energy than the sun by unit of mass and time. This staggering bioenergetic cost serves mostly synaptic... (Review)
Review
The human brain consumes five orders of magnitude more energy than the sun by unit of mass and time. This staggering bioenergetic cost serves mostly synaptic transmission and actin cytoskeleton dynamics. The peak of both brain bioenergetic demands and the age of onset for neurodevelopmental disorders is approximately 5 years of age. This correlation suggests that defects in the machinery that provides cellular energy would be causative and/or consequence of neurodevelopmental disorders. We explore this hypothesis from the perspective of the machinery required for the synthesis of the electron transport chain, an ATP-producing and NADH-consuming enzymatic cascade. The electron transport chain is constituted by nuclear- and mitochondrial-genome-encoded subunits. These subunits are synthesized by the 80S and the 55S ribosomes, which are segregated to the cytoplasm and the mitochondrial matrix, correspondingly. Mitochondrial protein synthesis by the 55S ribosome is the rate-limiting step in the synthesis of electron transport chain components, suggesting that mitochondrial protein synthesis is a bottleneck for tissues with high bionergetic demands. We discuss genetic defects in the human nuclear and mitochondrial genomes that affect these protein synthesis machineries and cause a phenotypic spectrum spanning autism spectrum disorders to neurodegeneration during neurodevelopment. We propose that dysregulated mitochondrial protein synthesis is a chief, yet understudied, causative mechanism of neurodevelopmental and behavioral disorders.
PubMed: 36060058
DOI: 10.1016/j.isci.2022.104920 -
Antioxidants & Redox Signaling Mar 2021Mitochondrial ribosomes (mitoribosomes) are organelles that translate mitochondrial messenger RNA in the matrix and, in mammals, have evolved to translate 13... (Review)
Review
Mitochondrial ribosomes (mitoribosomes) are organelles that translate mitochondrial messenger RNA in the matrix and, in mammals, have evolved to translate 13 polypeptides of the pathway that performs oxidative phosphorylation (OXPHOS). Although a number of devastating diseases result from defects in this mitochondrial translation apparatus, most are associated with genetic mutations and little is known about allelopathic defects caused by antibiotics, toxins, or nonproteinogenic amino acids. The levels of mitochondrial ribosomal subunits 12S and 16S ribosomal RNA (rRNA) in cells/tissues from patients carrying mutations in these genes have been associated with alterations in mitochondrial translation efficiency and with impaired OXPHOS activities, as well as with the severity of clinical phenotypes. In recent decades, important studies revealed a prominent role of mitochondrial dysfunction in Parkinson's disease (PD); however, the involvement of mitoribosomes remains largely unknown. Considering that mitoribosomal structure and function can determine the efficiency of OXPHOS and that an impaired mitochondrial respiratory chain is a common finding in PD, we argue that the mitoribosome may be key to disease onset and progression. With this review, we comprehensively integrate the available knowledge on the composition, assembly, and role of the mitoribosome in mitochondrial efficiency, reflecting on its possible involvement in the etiopathogenesis of this epidemic disease as an appealing research avenue. If a direct correlation between mitoribosome failure and PD pathology is demonstrated, these mitochondrial organelles will provide valuable early clinical markers and potentially attractive targets for the development of innovative PD-directed therapeutic agents.
Topics: Animals; Humans; Mitochondria; Mitochondrial Ribosomes; Parkinson Disease
PubMed: 32098485
DOI: 10.1089/ars.2019.7997 -
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 -
Biochimie Apr 2023Ribosomopathies are rare congenital disorders associated with defective ribosome biogenesis due to pathogenic variations in genes that encode proteins related to... (Review)
Review
Ribosomopathies are rare congenital disorders associated with defective ribosome biogenesis due to pathogenic variations in genes that encode proteins related to ribosome function and biogenesis. Defects in ribosome biogenesis result in a nucleolar stress response involving the TP53 tumor suppressor protein and impaired protein synthesis leading to a deregulated translational output. Despite the accepted notion that ribosomes are omnipresent and essential for all cells, most ribosomopathies show tissue-specific phenotypes affecting blood cells, hair, spleen, or skin. On the other hand, defects in mitochondrial ribosome biogenesis are associated with a range of clinical manifestations affecting more than one organ. Intriguingly, the deregulated ribosomal function is also a feature in several human malignancies with a selective upregulation or downregulation of specific ribosome components. Here, we highlight the clinical conditions associated with defective ribosome biogenesis in the nucleus and mitochondria with a description of the affected genes and the implicated pathways, along with a note on the treatment strategies currently available for these disorders.
Topics: Humans; Ribosomal Proteins; Mitochondrial Ribosomes; Ribosomes; Phenotype; Neoplasms; Mitochondria
PubMed: 36336106
DOI: 10.1016/j.biochi.2022.11.001 -
Mitochondrion May 2022Mitochondrial diseases are a group of genetic disorders characterized by dysfunctional mitochondria. Within eukaryotic cells, mitochondria contain their own ribosomes,... (Review)
Review
Mitochondrial diseases are a group of genetic disorders characterized by dysfunctional mitochondria. Within eukaryotic cells, mitochondria contain their own ribosomes, which synthesize small amounts of proteins, all of which are essential for the biogenesis of the oxidative phosphorylation system. The ribosome is an evolutionarily conserved macromolecular machine in nature both from a structural and functional point of view, universally responsible for the synthesis of proteins. Among the diseases afflicting humans, those of ribosomal origin - either cytoplasmic ribosomes (80S) or mitochondrial ribosomes (70S) - are relevant. These are inherited or acquired diseases most commonly caused by either ribosomal protein haploinsufficiency or defects in ribosome biogenesis. Here we review the scientific literature about the recent advances on changes in mitochondrial ribosomal structural and assembly proteins that are implicated in primary mitochondrial diseases and neurodegenerative disorders, and their possible connection with metalloid pollution and toxicity, with a focus on MRPL44, NAM9 (MNA6) and GEP3 (MTG3), whose lack or defect was associated with resistance to tellurite. Finally, we illustrate the suitability of yeast Saccharomyces cerevisiae (S. cerevisiae) and the nematode Caenorhabditis elegans (C. elegans) as model organisms for studying mitochondrial ribosome dysfunctions including those involved in human diseases.
Topics: Alzheimer Disease; Animals; Caenorhabditis elegans; Humans; Mitochondrial Diseases; RNA, Ribosomal; Ribosomal Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Tellurium
PubMed: 35218961
DOI: 10.1016/j.mito.2022.02.006 -
RNA Biology 2022In all living cells, the ribosome translates the genetic information carried by messenger RNAs (mRNAs) into proteins. The process of ribosome recycling, a key step... (Review)
Review
In all living cells, the ribosome translates the genetic information carried by messenger RNAs (mRNAs) into proteins. The process of ribosome recycling, a key step during protein synthesis that ensures ribosomal subunits remain available for new rounds of translation, has been largely overlooked. Despite being essential to the survival of the cell, several mechanistic aspects of ribosome recycling remain unclear. In eubacteria and mitochondria, recycling of the ribosome into subunits requires the concerted action of the ribosome recycling factor (RRF) and elongation factor G (EF-G). Recently, the conserved protein HflX was identified in bacteria as an alternative factor that recycles the ribosome under stress growth conditions. The homologue of HflX, the GTP-binding protein 6 (GTPBP6), has a dual role in mitochondrial translation by facilitating ribosome recycling and biogenesis. In this review, mechanisms of ribosome recycling in eubacteria and mitochondria are described based on structural studies of ribosome complexes.
Topics: Bacteria; Mitochondria; Peptide Elongation Factor G; Protein Biosynthesis; RNA, Messenger; Ribosomes
PubMed: 35485608
DOI: 10.1080/15476286.2022.2067712 -
Nature Communications Jun 2021Ribosome biogenesis requires auxiliary factors to promote folding and assembly of ribosomal proteins and RNA. Particularly, maturation of the peptidyl transferase center...
Ribosome biogenesis requires auxiliary factors to promote folding and assembly of ribosomal proteins and RNA. Particularly, maturation of the peptidyl transferase center (PTC) is mediated by conserved GTPases, but the molecular basis is poorly understood. Here, we define the mechanism of GTPase-driven maturation of the human mitochondrial large ribosomal subunit (mtLSU) using endogenous complex purification, in vitro reconstitution and cryo-EM. Structures of transient native mtLSU assembly intermediates that accumulate in GTPBP6-deficient cells reveal how the biogenesis factors GTPBP5, MTERF4 and NSUN4 facilitate PTC folding. Addition of recombinant GTPBP6 reconstitutes late mtLSU biogenesis in vitro and shows that GTPBP6 triggers a molecular switch and progression to a near-mature PTC state. Additionally, cryo-EM analysis of GTPBP6-treated mature mitochondrial ribosomes reveals the structural basis for the dual-role of GTPBP6 in ribosome biogenesis and recycling. Together, these results provide a framework for understanding step-wise PTC folding as a critical conserved quality control checkpoint.
Topics: Cryoelectron Microscopy; GTP-Binding Proteins; Humans; Methyltransferases; Mitochondrial Ribosomes; Models, Molecular; Monomeric GTP-Binding Proteins; Multiprotein Complexes; Organelle Biogenesis; Peptidyl Transferases; Protein Folding; RNA, Ribosomal; Ribosome Subunits, Large; Transcription Factors
PubMed: 34135319
DOI: 10.1038/s41467-021-23702-y -
Frontiers in Oncology 2022Next-generation sequencing and bioinformatics analyses have clearly revealed the roles of mitochondrial ribosomal genes in cancer development. Mitochondrial ribosomes... (Review)
Review
Next-generation sequencing and bioinformatics analyses have clearly revealed the roles of mitochondrial ribosomal genes in cancer development. Mitochondrial ribosomes are composed of three RNA components encoded by mitochondrial DNA and 82 specific protein components encoded by nuclear DNA. They synthesize mitochondrial inner membrane oxidative phosphorylation (OXPHOS)-related proteins and participate in various biological activities the regulation of energy metabolism and apoptosis. Mitochondrial ribosomal genes are strongly associated with clinical features such as prognosis and foci metastasis in patients with cancer. Accordingly, mitochondrial ribosomes have become an important focus of cancer research. We review recent advances in bioinformatics research that have explored the link between mitochondrial ribosomes and cancer, with a focus on the potential of mitochondrial ribosomal genes as biomarkers in cancer.
PubMed: 35719986
DOI: 10.3389/fonc.2022.835549 -
Molecular & Cellular Proteomics : MCP Aug 2023Proteomic studies in facioscapulohumeral muscular dystrophy (FSHD) could offer new insight into disease mechanisms underpinned by post-transcriptional processes. We used...
Proteomic studies in facioscapulohumeral muscular dystrophy (FSHD) could offer new insight into disease mechanisms underpinned by post-transcriptional processes. We used stable isotope (deuterium oxide; DO) labeling and peptide mass spectrometry to investigate the abundance and turnover rates of proteins in cultured muscle cells from two individuals affected by FSHD and their unaffected siblings (UASb). We measured the abundance of 4420 proteins and the turnover rate of 2324 proteins in each (n = 4) myoblast sample. FSHD myoblasts exhibited a greater abundance but slower turnover rate of subunits of mitochondrial respiratory complexes and mitochondrial ribosomal proteins, which may indicate an accumulation of "older" less viable mitochondrial proteins in myoblasts from individuals affected by FSHD. Treatment with a 2'-O-methoxyethyl modified antisense oligonucleotide targeting exon 3 of the double homeobox 4 (DUX4) transcript tended to reverse mitochondrial protein dysregulation in FSHD myoblasts, indicating the effect on mitochondrial proteins may be a DUX4-dependent mechanism. Our results highlight the importance of post-transcriptional processes and protein turnover in FSHD pathology and provide a resource for the FSHD research community to explore this burgeoning aspect of FSHD.
Topics: Humans; Muscular Dystrophy, Facioscapulohumeral; Proteome; Proteomics; Homeodomain Proteins; Myoblasts; Muscle, Skeletal
PubMed: 37353005
DOI: 10.1016/j.mcpro.2023.100605