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FEBS Open Bio Jun 2024Mitoribosome biogenesis is a complex process involving RNA elements encoded in the mitochondrial genome and mitoribosomal proteins typically encoded in the nuclear... (Review)
Review
Mitoribosome biogenesis is a complex process involving RNA elements encoded in the mitochondrial genome and mitoribosomal proteins typically encoded in the nuclear genome. This process is orchestrated by extra-ribosomal proteins, nucleus-encoded assembly factors, which play roles across all assembly stages to coordinate ribosomal RNA processing and maturation with the sequential association of ribosomal proteins. Both biochemical studies and recent cryo-EM structures of mammalian mitoribosomes have provided insights into their assembly process. In this article, we will briefly outline the current understanding of mammalian mitoribosome biogenesis pathways and the factors involved. Special attention is devoted to the recent identification of iron-sulfur clusters as structural components of the mitoribosome and a small subunit assembly factor, the existence of redox-sensitive cysteines in mitoribosome proteins and assembly factors, and the role they may play as redox sensor units to regulate mitochondrial translation under stress.
PubMed: 38849194
DOI: 10.1002/2211-5463.13844 -
Trends in Cell Biology Sep 2023Most mitochondrial proteins are synthesized in the cytosol and transported into mitochondria by protein translocases. Yet, mitochondria contain their own genome and gene... (Review)
Review
Most mitochondrial proteins are synthesized in the cytosol and transported into mitochondria by protein translocases. Yet, mitochondria contain their own genome and gene expression system, which generates proteins that are inserted in the inner membrane by the oxidase assembly (OXA) insertase. OXA contributes to targeting proteins from both genetic origins. Recent data provides insights into how OXA cooperates with the mitochondrial ribosome during synthesis of mitochondrial-encoded proteins. A picture of OXA emerges in which it coordinates insertion of OXPHOS core subunits and their assembly into protein complexes but also participates in the biogenesis of select imported proteins. These functions position the OXA as a multifunctional protein insertase that facilitates protein transport, assembly, and stability at the inner membrane.
Topics: Humans; Oxidoreductases; Electron Transport Complex IV; Mitochondria; Mitochondrial Proteins; Carrier Proteins
PubMed: 36863885
DOI: 10.1016/j.tcb.2023.02.001 -
Trends in Cell Biology Oct 2017Mitochondria maintained a genome during evolution to synthesize core subunits of the oxidative phosphorylation system. Expression of the mitochondrial genome requires... (Review)
Review
Mitochondria maintained a genome during evolution to synthesize core subunits of the oxidative phosphorylation system. Expression of the mitochondrial genome requires intraorganellar replication, transcription, and translation. Membrane-associated ribosomes translate mitochondrial-encoded proteins and facilitate co-translational insertion of newly synthesized polypeptides into the inner membrane. Considering that mitochondrial-encoded proteins assemble with imported, nuclear-encoded proteins into enzyme complexes of the oxidative phosphorylation system, it is expected that expression of mitochondrial genes should adapt to the availability of their nuclear-encoded partners. Recent work shows that mitochondrial translation is influenced by the cellular environment. We discuss how mitochondrial translation is affected by the cellular environment and propose models of translational plasticity that modulate mitochondrial translation in response to the availability of imported proteins.
Topics: Animals; Humans; Mitochondria; Mitochondrial Proteins; Multienzyme Complexes; Nuclear Proteins; Oxidative Phosphorylation; Protein Biosynthesis; Protein Transport; RNA, Messenger; Ribosomes
PubMed: 28606446
DOI: 10.1016/j.tcb.2017.05.004 -
American Journal of Physiology. Lung... Apr 2022Mitochondria are involved in a variety of critical cellular functions, and their impairment drives cell injury. The mitochondrial ribosome (mitoribosome) is responsible... (Review)
Review
Mitochondria are involved in a variety of critical cellular functions, and their impairment drives cell injury. The mitochondrial ribosome (mitoribosome) is responsible for the protein synthesis of mitochondrial DNA-encoded genes. These proteins are involved in oxidative phosphorylation, respiration, and ATP production required in the cell. Mitoribosome components originate from both mitochondrial and nuclear genomes. Their dysfunction can be caused by impaired mitochondrial protein synthesis or mitoribosome misassembly, leading to a decline in mitochondrial translation. This decrease can trigger mitochondrial ribosomal stress and contribute to pulmonary cell injury, death, and diseases. This review focuses on the contribution of the impaired mitoribosome structural components and function to respiratory disease pathophysiology. We present recent findings in the fields of lung cancer, chronic obstructive pulmonary disease, interstitial lung disease, and asthma. We also include reports on the mitoribosome dysfunction in pulmonary hypertension, high-altitude pulmonary edema, and bacterial and viral infections. Studies of the mitoribosome alterations in respiratory diseases can lead to novel therapeutic targets.
Topics: Humans; Lung Diseases; Mitochondria; Mitochondrial Proteins; Mitochondrial Ribosomes; Protein Biosynthesis
PubMed: 34873929
DOI: 10.1152/ajplung.00078.2021 -
Human Molecular Genetics May 2024Human mitochondrial DNA is one of the most simplified cellular genomes and facilitates compartmentalized gene expression. Within the organelle, there is no physical... (Review)
Review
Human mitochondrial DNA is one of the most simplified cellular genomes and facilitates compartmentalized gene expression. Within the organelle, there is no physical barrier to separate transcription and translation, nor is there evidence that quality control surveillance pathways are active to prevent translation on faulty mRNA transcripts. Mitochondrial ribosomes synthesize 13 hydrophobic proteins that require co-translational insertion into the inner membrane of the organelle. To maintain the integrity of the inner membrane, which is essential for organelle function, requires responsive quality control mechanisms to recognize aberrations in protein synthesis. In this review, we explore how defects in mitochondrial protein synthesis can arise due to the culmination of inherent mistakes that occur throughout the steps of gene expression. In turn, we examine the stepwise series of quality control processes that are needed to eliminate any mistakes that would perturb organelle homeostasis. We aim to provide an integrated view on the quality control mechanisms of mitochondrial protein synthesis and to identify promising avenues for future research.
Topics: Humans; Protein Biosynthesis; Mitochondrial Proteins; Mitochondria; DNA, Mitochondrial; RNA, Messenger; Mitochondrial Ribosomes; Animals
PubMed: 38280230
DOI: 10.1093/hmg/ddae012 -
Science (New York, N.Y.) Feb 2021Mitochondrial ribosomes (mitoribosomes) are tethered to the mitochondrial inner membrane to facilitate the cotranslational membrane insertion of the synthesized...
Mitochondrial ribosomes (mitoribosomes) are tethered to the mitochondrial inner membrane to facilitate the cotranslational membrane insertion of the synthesized proteins. We report cryo-electron microscopy structures of human mitoribosomes with nascent polypeptide, bound to the insertase oxidase assembly 1-like (OXA1L) through three distinct contact sites. OXA1L binding is correlated with a series of conformational changes in the mitoribosomal large subunit that catalyze the delivery of newly synthesized polypeptides. The mechanism relies on the folding of mL45 inside the exit tunnel, forming two specific constriction sites that would limit helix formation of the nascent chain. A gap is formed between the exit and the membrane, making the newly synthesized proteins accessible. Our data elucidate the basis by which mitoribosomes interact with the OXA1L insertase to couple protein synthesis and membrane delivery.
Topics: Cryoelectron Microscopy; Electron Transport Complex IV; Humans; Membrane Proteins; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Mitochondrial Ribosomes; Models, Molecular; Nuclear Proteins; Protein Binding; Protein Biosynthesis; Protein Conformation; Protein Folding; Ribosomes
PubMed: 33602856
DOI: 10.1126/science.abe0763 -
Journal of Proteome Research Apr 2022Advanced analytic techniques, such as ribosome profiling and mass spectrometry, as well as improved bioinformatics technology, have promoted the field of genome... (Review)
Review
Advanced analytic techniques, such as ribosome profiling and mass spectrometry, as well as improved bioinformatics technology, have promoted the field of genome annotation forward and have identified thousands of likely coding short open reading frames (sORFs) in the human genome. The discovery of sORFs and their products allows us to realize that the complexity of the human genome is far greater than previously assumed. Here, we provide a review of human micropeptides encoded by various transcripts such as mitochondrial rRNAs, long noncoding RNAs, circular RNAs, upstream of mRNAs, and so on.
Topics: Computational Biology; Genome, Human; Humans; Open Reading Frames; Peptides; Ribosomes
PubMed: 35253438
DOI: 10.1021/acs.jproteome.1c00889 -
Cell Cycle (Georgetown, Tex.) 2015The ribosome is a structurally and functionally conserved macromolecular machine universally responsible for catalyzing protein synthesis. Within eukaryotic cells,... (Review)
Review
The ribosome is a structurally and functionally conserved macromolecular machine universally responsible for catalyzing protein synthesis. Within eukaryotic cells, mitochondria contain their own ribosomes (mitoribosomes), which synthesize a handful of proteins, all essential for the biogenesis of the oxidative phosphorylation system. High-resolution cryo-EM structures of the yeast, porcine and human mitoribosomal subunits and of the entire human mitoribosome have uncovered a wealth of new information to illustrate their evolutionary divergence from their bacterial ancestors and their adaptation to synthesis of highly hydrophobic membrane proteins. With such structural data becoming available, one of the most important remaining questions is that of the mitoribosome assembly pathway and factors involved. The regulation of mitoribosome biogenesis is paramount to mitochondrial respiration, and thus to cell viability, growth and differentiation. Moreover, mutations affecting the rRNA and protein components produce severe human mitochondrial disorders. Despite its biological and biomedical significance, knowledge on mitoribosome biogenesis and its deviations from the much-studied bacterial ribosome assembly processes is scarce, especially the order of rRNA processing and assembly events and the regulatory factors required to achieve fully functional particles. This article focuses on summarizing the current available information on mitoribosome assembly pathway, factors that form the mitoribosome assembly machinery, and the effect of defective mitoribosome assembly on human health.
Topics: GTP Phosphohydrolases; Humans; MicroRNAs; Mitochondrial Diseases; Mitochondrial Ribosomes; Protein Structure, Quaternary; RNA Helicases; RNA, Ribosomal; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Trans-Activators
PubMed: 26030272
DOI: 10.1080/15384101.2015.1053672 -
Blood May 2023Pathogenic missense variants in SLFN14, which encode an RNA endoribonuclease protein that regulates ribosomal RNA (rRNA) degradation, are known to cause inherited...
Pathogenic missense variants in SLFN14, which encode an RNA endoribonuclease protein that regulates ribosomal RNA (rRNA) degradation, are known to cause inherited thrombocytopenia (TP) with impaired platelet aggregation and adenosine triphosphate secretion. Despite mild laboratory defects, the patients displayed an obvious bleeding phenotype. However, the function of SLFN14 in megakaryocyte (MK) and platelet biology remains unknown. This study aimed to model the disease in an immortalized MK cell line (imMKCL) and to characterize the platelet transcriptome in patients with the SLFN14 K219N variant. MK derived from heterozygous and homozygous SLFN14 K219N imMKCL and stem cells of blood from patients mainly presented with a defect in proplatelet formation and mitochondrial organization. SLFN14-defective platelets and mature MK showed signs of rRNA degradation; however, this was absent in undifferentiated imMKCL cells and granulocytes. Total platelet RNA was sequenced in 2 patients and 19 healthy controls. Differential gene expression analysis yielded 2999 and 2888 significantly (|log2 fold change| >1, false discovery rate <0.05) up- and downregulated genes, respectively. Remarkably, these downregulated genes were not enriched in any biological pathway, whereas upregulated genes were enriched in pathways involved in (mitochondrial) translation and transcription, with a significant upregulation of 134 ribosomal protein genes (RPGs). The upregulation of mitochondrial RPGs through increased mammalian target of rapamycin complex 1 (mTORC1) signaling in SLFN14 K219N MK seems to be a compensatory response to rRNA degradation. mTORC1 inhibition with rapamycin resulted in further enhanced rRNA degradation in SLFN14 K219N MK. Taken together, our study indicates dysregulation of mTORC1 coordinated ribosomal biogenesis is the disease mechanism for SLFN14-related TP.
Topics: Humans; Thrombocytopenia; Blood Platelets; Ribosomes; Megakaryocytes; Ribosomal Proteins; Mechanistic Target of Rapamycin Complex 1; RNA
PubMed: 36790527
DOI: 10.1182/blood.2022017712 -
Seminars in Cancer Biology Dec 2017Mitochondria play fundamental roles in the regulation of life and death of eukaryotic cells. They mediate aerobic energy conversion through the oxidative phosphorylation... (Review)
Review
Mitochondria play fundamental roles in the regulation of life and death of eukaryotic cells. They mediate aerobic energy conversion through the oxidative phosphorylation (OXPHOS) system, and harbor and control the intrinsic pathway of apoptosis. As a descendant of a bacterial endosymbiont, mitochondria retain a vestige of their original genome (mtDNA), and its corresponding full gene expression machinery. Proteins encoded in the mtDNA, all components of the multimeric OXPHOS enzymes, are synthesized in specialized mitochondrial ribosomes (mitoribosomes). Mitoribosomes are therefore essential in the regulation of cellular respiration. Additionally, an increasing body of literature has been reporting an alternative role for several mitochondrial ribosomal proteins as apoptosis-inducing factors. No surprisingly, the expression of genes encoding for mitoribosomal proteins, mitoribosome assembly factors and mitochondrial translation factors is modified in numerous cancers, a trait that has been linked to tumorigenesis and metastasis. In this article, we will review the current knowledge regarding the dual function of mitoribosome components in protein synthesis and apoptosis and their association with cancer susceptibility and development. We will also highlight recent developments in targeting mitochondrial ribosomes for the treatment of cancer.
Topics: Animals; Apoptosis; Biomarkers; Gene Expression Regulation, Neoplastic; Humans; Mitochondria; Mitochondrial Ribosomes; Molecular Targeted Therapy; Neoplasms; Oxidative Phosphorylation; Protein Biosynthesis; Ribosomal Proteins; Signal Transduction
PubMed: 28445780
DOI: 10.1016/j.semcancer.2017.04.004