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Annual Review of Biochemistry Jun 2016Mitochondrial ribosomes (mitoribosomes) perform protein synthesis inside mitochondria, the organelles responsible for energy conversion and adenosine triphosphate... (Review)
Review
Mitochondrial ribosomes (mitoribosomes) perform protein synthesis inside mitochondria, the organelles responsible for energy conversion and adenosine triphosphate production in eukaryotic cells. Throughout evolution, mitoribosomes have become functionally specialized for synthesizing mitochondrial membrane proteins, and this has been accompanied by large changes to their structure and composition. We review recent high-resolution structural data that have provided unprecedented insight into the structure and function of mitoribosomes in mammals and fungi.
Topics: Animals; Anti-Bacterial Agents; Biological Evolution; Carboxylic Ester Hydrolases; DNA, Mitochondrial; Mammals; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Mitochondrial Ribosomes; Models, Molecular; Protein Biosynthesis; RNA, Messenger; RNA, Transfer; Ribosome Subunits; Saccharomyces cerevisiae
PubMed: 27023846
DOI: 10.1146/annurev-biochem-060815-014343 -
Cells Jul 2021Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. HCC progression and metastasis are closely related to altered mitochondrial... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. HCC progression and metastasis are closely related to altered mitochondrial metabolism, including mitochondrial stress responses, metabolic reprogramming, and mitoribosomal defects. Mitochondrial oxidative phosphorylation (OXPHOS) defects and reactive oxygen species (ROS) production are attributed to mitochondrial dysfunction. In response to oxidative stress caused by increased ROS production, misfolded or unfolded proteins can accumulate in the mitochondrial matrix, leading to initiation of the mitochondrial unfolded protein response (UPR). The mitokines FGF21 and GDF15 are upregulated during UPR and their levels are positively correlated with liver cancer development, progression, and metastasis. In addition, mitoribosome biogenesis is important for the regulation of mitochondrial respiration, cell viability, and differentiation. Mitoribosomal defects cause OXPHOS impairment, mitochondrial dysfunction, and increased production of ROS, which are associated with HCC progression in mouse models and human HCC patients. In this paper, we focus on the role of mitochondrial metabolic signatures in the development and progression of HCC. Furthermore, we provide a comprehensive review of cell autonomous and cell non-autonomous mitochondrial stress responses during HCC progression and metastasis.
Topics: Animals; Carcinoma, Hepatocellular; Disease Progression; Energy Metabolism; Humans; Liver Neoplasms; Metabolome; Mitochondria, Liver; Mitochondrial Ribosomes; Proteostasis; Reactive Oxygen Species; Signal Transduction; Unfolded Protein Response
PubMed: 34440674
DOI: 10.3390/cells10081901 -
International Journal of Molecular... May 2021Cytosolic ribosomes (cytoribosomes) are macromolecular ribonucleoprotein complexes that are assembled from ribosomal RNA and ribosomal proteins, which are essential for... (Review)
Review
Cytosolic ribosomes (cytoribosomes) are macromolecular ribonucleoprotein complexes that are assembled from ribosomal RNA and ribosomal proteins, which are essential for protein biosynthesis. Mitochondrial ribosomes (mitoribosomes) perform translation of the proteins essential for the oxidative phosphorylation system. The biogenesis of cytoribosomes and mitoribosomes includes ribosomal RNA processing, modification and binding to ribosomal proteins and is assisted by numerous biogenesis factors. This is a major energy-consuming process in the cell and, therefore, is highly coordinated and sensitive to several cellular stressors. In mitochondria, the regulation of mitoribosome biogenesis is essential for cellular respiration, a process linked to cell growth and proliferation. This review briefly overviews the key stages of cytosolic and mitochondrial ribosome biogenesis; summarizes the main steps of ribosome biogenesis alterations occurring during tumorigenesis, highlighting the changes in the expression level of cytosolic ribosomal proteins (CRPs) and mitochondrial ribosomal proteins (MRPs) in different types of tumors; focuses on the currently available information regarding the extra-ribosomal functions of CRPs and MRPs correlated to cancer; and discusses the role of CRPs and MRPs as biomarkers and/or molecular targets in cancer treatment.
Topics: Animals; Apoptosis; Autophagy; Cell Cycle; Cell Movement; Cell Nucleolus; Cell Transformation, Neoplastic; Cytosol; DNA Repair; Endoplasmic Reticulum Stress; Eukaryotic Cells; Gene Expression Regulation, Neoplastic; Genetic Therapy; Humans; Mitochondria; Mitochondrial Proteins; Neoplasm Proteins; Neoplasms; Organelle Biogenesis; RNA Precursors; RNA Processing, Post-Transcriptional; RNA, Mitochondrial; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 34071057
DOI: 10.3390/ijms22115496 -
Annual Review of Biochemistry Jun 2016Mammalian mitochondrial DNA (mtDNA) encodes 13 proteins that are essential for the function of the oxidative phosphorylation system, which is composed of four... (Review)
Review
Mammalian mitochondrial DNA (mtDNA) encodes 13 proteins that are essential for the function of the oxidative phosphorylation system, which is composed of four respiratory-chain complexes and adenosine triphosphate (ATP) synthase. Remarkably, the maintenance and expression of mtDNA depend on the mitochondrial import of hundreds of nuclear-encoded proteins that control genome maintenance, replication, transcription, RNA maturation, and mitochondrial translation. The importance of this complex regulatory system is underscored by the identification of numerous mutations of nuclear genes that impair mtDNA maintenance and expression at different levels, causing human mitochondrial diseases with pleiotropic clinical manifestations. The basic scientific understanding of the mechanisms controlling mtDNA function has progressed considerably during the past few years, thanks to advances in biochemistry, genetics, and structural biology. The challenges for the future will be to understand how mtDNA maintenance and expression are regulated and to what extent direct intramitochondrial cross talk between different processes, such as transcription and translation, is important.
Topics: Animals; Biological Evolution; Cell Nucleus; DNA Replication; DNA, Mitochondrial; Electron Transport; Gene Expression Regulation; Mammals; Mitochondria; Mitochondrial Proteins; Mitochondrial Ribosomes; Models, Molecular; Oxidative Phosphorylation; Protein Biosynthesis; Protein Transport; Signal Transduction; Transcription, Genetic
PubMed: 27023847
DOI: 10.1146/annurev-biochem-060815-014402 -
Nature Feb 2018Folates enable the activation and transfer of one-carbon units for the biosynthesis of purines, thymidine and methionine. Antifolates are important immunosuppressive and...
Folates enable the activation and transfer of one-carbon units for the biosynthesis of purines, thymidine and methionine. Antifolates are important immunosuppressive and anticancer agents. In proliferating lymphocytes and human cancers, mitochondrial folate enzymes are particularly strongly upregulated. This in part reflects the need for mitochondria to generate one-carbon units and export them to the cytosol for anabolic metabolism. The full range of uses of folate-bound one-carbon units in the mitochondrial compartment itself, however, has not been thoroughly explored. Here we show that loss of the catalytic activity of the mitochondrial folate enzyme serine hydroxymethyltransferase 2 (SHMT2), but not of other folate enzymes, leads to defective oxidative phosphorylation in human cells due to impaired mitochondrial translation. We find that SHMT2, presumably by generating mitochondrial 5,10-methylenetetrahydrofolate, provides methyl donors to produce the taurinomethyluridine base at the wobble position of select mitochondrial tRNAs. Mitochondrial ribosome profiling in SHMT2-knockout human cells reveals that the lack of this modified base causes defective translation, with preferential mitochondrial ribosome stalling at certain lysine (AAG) and leucine (UUG) codons. This results in the impaired expression of respiratory chain enzymes. Stalling at these specific codons also occurs in certain inborn errors of mitochondrial metabolism. Disruption of whole-cell folate metabolism, by either folate deficiency or antifolate treatment, also impairs the respiratory chain. In summary, mammalian mitochondria use folate-bound one-carbon units to methylate tRNA, and this modification is required for mitochondrial translation and thus oxidative phosphorylation.
Topics: Aminohydrolases; Biocatalysis; Carrier Proteins; Codon; Electron Transport; Folic Acid; Folic Acid Antagonists; GTP-Binding Proteins; Glycine Hydroxymethyltransferase; Guanosine; HCT116 Cells; HEK293 Cells; Humans; Leucine; Lysine; Methylation; Methylenetetrahydrofolate Dehydrogenase (NADP); Mitochondria; Multifunctional Enzymes; Oxidative Phosphorylation; Protein Biosynthesis; RNA, Transfer; RNA-Binding Proteins; Ribosomes; Sarcosine; Tetrahydrofolates; Thymine Nucleotides
PubMed: 29364879
DOI: 10.1038/nature25460 -
Nature Reviews. Clinical Oncology Jan 2017Awareness that the metabolic phenotype of cells within tumours is heterogeneous - and distinct from that of their normal counterparts - is growing. In general, tumour... (Review)
Review
Awareness that the metabolic phenotype of cells within tumours is heterogeneous - and distinct from that of their normal counterparts - is growing. In general, tumour cells metabolize glucose, lactate, pyruvate, hydroxybutyrate, acetate, glutamine, and fatty acids at much higher rates than their nontumour equivalents; however, the metabolic ecology of tumours is complex because they contain multiple metabolic compartments, which are linked by the transfer of these catabolites. This metabolic variability and flexibility enables tumour cells to generate ATP as an energy source, while maintaining the reduction-oxidation (redox) balance and committing resources to biosynthesis - processes that are essential for cell survival, growth, and proliferation. Importantly, experimental evidence indicates that metabolic coupling between cell populations with different, complementary metabolic profiles can induce cancer progression. Thus, targeting the metabolic differences between tumour and normal cells holds promise as a novel anticancer strategy. In this Review, we discuss how cancer cells reprogramme their metabolism and that of other cells within the tumour microenvironment in order to survive and propagate, thus driving disease progression; in particular, we highlight potential metabolic vulnerabilities that might be targeted therapeutically.
Topics: Acetyl Coenzyme A; Adaptation, Physiological; Amino Acids; Antineoplastic Agents; Antioxidants; Autophagy; Blood Glucose; Energy Metabolism; Epigenomics; Fatty Acids; Genetic Heterogeneity; Glutamic Acid; Glutamine; Humans; Ketone Bodies; Lactic Acid; Lipids; Mitochondria; Mitochondrial Ribosomes; Neoplasms; Nucleic Acids; Oxidative Stress; Pyruvic Acid; TOR Serine-Threonine Kinases; Transcription Factors; Tumor Microenvironment
PubMed: 27141887
DOI: 10.1038/nrclinonc.2016.60 -
Methods in Molecular Biology (Clifton,... 2023Mitoribosome biogenesis is a complex and energetically costly process that involves RNA elements encoded in the mitochondrial genome and mitoribosomal proteins most...
Mitoribosome biogenesis is a complex and energetically costly process that involves RNA elements encoded in the mitochondrial genome and mitoribosomal proteins most frequently encoded in the nuclear genome. The process is catalyzed by extra-ribosomal proteins, nucleus-encoded assembly factors that act in all stages of the assembly process to coordinate the processing and maturation of ribosomal RNAs with the hierarchical association of ribosomal proteins. Biochemical studies and recent cryo-EM structures of mammalian mitoribosomes have provided hints regarding their assembly. In this general concept chapter, we will briefly describe the current knowledge, mainly regarding the mammalian mitoribosome biogenesis pathway and factors involved, and will emphasize the biological sources and approaches that have been applied to advance the field.
Topics: Animals; Mitochondrial Ribosomes; Ribosomal Proteins; RNA, Ribosomal; Mammals; Mitochondrial Proteins
PubMed: 37166630
DOI: 10.1007/978-1-0716-3171-3_3 -
Cell Metabolism Dec 2016Oxidative phosphorylation (OXPHOS) is the major pathway for ATP production in humans. Deficiencies in OXPHOS can arise from mutations in either mitochondrial or nuclear...
Oxidative phosphorylation (OXPHOS) is the major pathway for ATP production in humans. Deficiencies in OXPHOS can arise from mutations in either mitochondrial or nuclear genomes and comprise the largest collection of inborn errors of metabolism. At present we lack a complete catalog of human genes and pathways essential for OXPHOS. Here we introduce a genome-wide CRISPR "death screen" that actively selects dying cells to reveal human genes required for OXPHOS, inspired by the classic observation that human cells deficient in OXPHOS survive in glucose but die in galactose. We report 191 high-confidence hits essential for OXPHOS, including 72 underlying known OXPHOS diseases. Our screen reveals a functional module consisting of NGRN, WBSCR16, RPUSD3, RPUSD4, TRUB2, and FASTKD2 that regulates the mitochondrial 16S rRNA and intra-mitochondrial translation. Our work yields a rich catalog of genes required for OXPHOS and, more generally, demonstrates the power of death screening for functional genomic analysis.
Topics: Cell Death; Clustered Regularly Interspaced Short Palindromic Repeats; Galactose; Genes, Mitochondrial; Genome; Glucose; HEK293 Cells; HeLa Cells; Humans; K562 Cells; Mitochondria; Oxidative Phosphorylation; Phenotype; Protein Biosynthesis; RNA, Ribosomal, 16S; Reproducibility of Results
PubMed: 27667664
DOI: 10.1016/j.cmet.2016.08.017 -
Cell Metabolism May 2021Mitochondria have an independent genome (mtDNA) and protein synthesis machinery that coordinately activate for mitochondrial generation. Here, we report that the Krebs...
Mitochondria have an independent genome (mtDNA) and protein synthesis machinery that coordinately activate for mitochondrial generation. Here, we report that the Krebs cycle intermediate fumarate links metabolism to mitobiogenesis through binding to malic enzyme 2 (ME2). Mechanistically, fumarate binds ME2 with two complementary consequences. First, promoting the formation of ME2 dimers, which activate deoxyuridine 5'-triphosphate nucleotidohydrolase (DUT). DUT fosters thymidine generation and an increase of mtDNA. Second, fumarate-induced ME2 dimers abrogate ME2 monomer binding to mitochondrial ribosome protein L45, freeing it for mitoribosome assembly and mtDNA-encoded protein production. Methylation of the ME2-fumarate binding site by protein arginine methyltransferase-1 inhibits fumarate signaling to constrain mitobiogenesis. Notably, acute myeloid leukemia is highly dependent on mitochondrial function and is sensitive to targeting of the fumarate-ME2 axis. Therefore, mitobiogenesis can be manipulated in normal and malignant cells through ME2, an unanticipated governor of mitochondrial biomass production that senses nutrient availability through fumarate.
Topics: Animals; Cell Line; Citric Acid Cycle; DNA, Mitochondrial; Dimerization; Fumarates; Humans; Leukemia; Malate Dehydrogenase; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mitochondria; Protein Binding; Protein-Arginine N-Methyltransferases; Pyrophosphatases; RNA Interference; RNA, Small Interfering; Ribosomal Proteins; Thymidine
PubMed: 33770508
DOI: 10.1016/j.cmet.2021.03.003 -
FEBS Letters Apr 2021Mitochondria control life and death in eukaryotic cells. Harboring a unique circular genome, a by-product of an ancient endosymbiotic event, mitochondria maintains a... (Review)
Review
Mitochondria control life and death in eukaryotic cells. Harboring a unique circular genome, a by-product of an ancient endosymbiotic event, mitochondria maintains a specialized and evolutionary divergent protein synthesis machinery, the mitoribosome. Mitoribosome biogenesis depends on elements encoded in both the mitochondrial genome (the RNA components) and the nuclear genome (all ribosomal proteins and assembly factors). Recent cryo-EM structures of mammalian mitoribosomes have illuminated their composition and provided hints regarding their assembly and elusive mitochondrial translation mechanisms. A growing body of literature involves the mitoribosome in inherited primary mitochondrial disorders. Mutations in genes encoding mitoribosomal RNAs, proteins, and assembly factors impede mitoribosome biogenesis, causing protein synthesis defects that lead to respiratory chain failure and mitochondrial disorders such as encephalo- and cardiomyopathy, deafness, neuropathy, and developmental delays. In this article, we review the current fundamental understanding of mitoribosome assembly and function, and the clinical landscape of mitochondrial disorders driven by mutations in mitoribosome components and assembly factors, to portray how basic and clinical studies combined help us better understand both mitochondrial biology and medicine.
Topics: Animals; Genome, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Mitochondrial Ribosomes; Mutation; Protein Biosynthesis; Ribosomal Proteins
PubMed: 33314036
DOI: 10.1002/1873-3468.14024