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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 -
Nature Jun 2022Mitochondria are epicentres of eukaryotic metabolism and bioenergetics. Pioneering efforts in recent decades have established the core protein componentry of these...
Mitochondria are epicentres of eukaryotic metabolism and bioenergetics. Pioneering efforts in recent decades have established the core protein componentry of these organelles and have linked their dysfunction to more than 150 distinct disorders. Still, hundreds of mitochondrial proteins lack clear functions, and the underlying genetic basis for approximately 40% of mitochondrial disorders remains unresolved. Here, to establish a more complete functional compendium of human mitochondrial proteins, we profiled more than 200 CRISPR-mediated HAP1 cell knockout lines using mass spectrometry-based multiomics analyses. This effort generated approximately 8.3 million distinct biomolecule measurements, providing a deep survey of the cellular responses to mitochondrial perturbations and laying a foundation for mechanistic investigations into protein function. Guided by these data, we discovered that PIGY upstream open reading frame (PYURF) is an S-adenosylmethionine-dependent methyltransferase chaperone that supports both complex I assembly and coenzyme Q biosynthesis and is disrupted in a previously unresolved multisystemic mitochondrial disorder. We further linked the putative zinc transporter SLC30A9 to mitochondrial ribosomes and OxPhos integrity and established RAB5IF as the second gene harbouring pathogenic variants that cause cerebrofaciothoracic dysplasia. Our data, which can be explored through the interactive online MITOMICS.app resource, suggest biological roles for many other orphan mitochondrial proteins that still lack robust functional characterization and define a rich cell signature of mitochondrial dysfunction that can support the genetic diagnosis of mitochondrial diseases.
Topics: Cation Transport Proteins; Cell Cycle Proteins; Energy Metabolism; Humans; Mass Spectrometry; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Transcription Factors; rab5 GTP-Binding Proteins
PubMed: 35614220
DOI: 10.1038/s41586-022-04765-3 -
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 -
Signal Transduction and Targeted Therapy Feb 2021In addition to their use in relieving the symptoms of various diseases, ketogenic diets (KDs) have also been adopted by healthy individuals to prevent being overweight....
In addition to their use in relieving the symptoms of various diseases, ketogenic diets (KDs) have also been adopted by healthy individuals to prevent being overweight. Herein, we reported that prolonged KD exposure induced cardiac fibrosis. In rats, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis. Mechanistically, increased levels of the ketone body β-hydroxybutyrate (β-OHB), an HDAC2 inhibitor, promoted histone acetylation of the Sirt7 promoter and activated Sirt7 transcription. This in turn inhibited the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis, leading to cardiomyocyte apoptosis and cardiac fibrosis. Exogenous β-OHB administration mimicked the effects of a KD in rats. Notably, increased β-OHB levels and SIRT7 expression, decreased mitochondrial biogenesis, and increased cardiac fibrosis were detected in human atrial fibrillation heart tissues. Our results highlighted the unknown detrimental effects of KDs and provided insights into strategies for preventing cardiac fibrosis in patients for whom KDs are medically necessary.
Topics: 3-Hydroxybutyric Acid; Acetylation; Animals; Apoptosis; Diet, Ketogenic; Disease Models, Animal; Fasting; Fibrosis; Gene Expression Regulation; Histone Deacetylase 2; Histones; Humans; Ketone Bodies; Male; Myocytes, Cardiac; Organelle Biogenesis; Rats; Sirtuins
PubMed: 33558457
DOI: 10.1038/s41392-020-00411-4 -
Nature Feb 2023Mitochondria have crucial roles in cellular energetics, metabolism, signalling and quality control. They contain around 1,000 different proteins that often assemble into...
Mitochondria have crucial roles in cellular energetics, metabolism, signalling and quality control. They contain around 1,000 different proteins that often assemble into complexes and supercomplexes such as respiratory complexes and preprotein translocases. The composition of the mitochondrial proteome has been characterized; however, the organization of mitochondrial proteins into stable and dynamic assemblies is poorly understood for major parts of the proteome. Here we report quantitative mapping of mitochondrial protein assemblies using high-resolution complexome profiling of more than 90% of the yeast mitochondrial proteome, termed MitCOM. An analysis of the MitCOM dataset resolves >5,200 protein peaks with an average of six peaks per protein and demonstrates a notable complexity of mitochondrial protein assemblies with distinct appearance for respiration, metabolism, biogenesis, dynamics, regulation and redox processes. We detect interactors of the mitochondrial receptor for cytosolic ribosomes, of prohibitin scaffolds and of respiratory complexes. The identification of quality-control factors operating at the mitochondrial protein entry gate reveals pathways for preprotein ubiquitylation, deubiquitylation and degradation. Interactions between the peptidyl-tRNA hydrolase Pth2 and the entry gate led to the elucidation of a constitutive pathway for the removal of preproteins. The MitCOM dataset-which is accessible through an interactive profile viewer-is a comprehensive resource for the identification, organization and interaction of mitochondrial machineries and pathways.
Topics: Carrier Proteins; Mitochondria; Mitochondrial Proteins; Protein Transport; Proteome; Saccharomyces cerevisiae; Fungal Proteins; Cell Respiration; Ribosomes; Datasets as Topic
PubMed: 36697829
DOI: 10.1038/s41586-022-05641-w -
Molecular Cell Jun 2023Localized translation is vital to polarized cells and requires precise and robust distribution of different mRNAs and ribosomes across the cell. However, the underlying...
Localized translation is vital to polarized cells and requires precise and robust distribution of different mRNAs and ribosomes across the cell. However, the underlying molecular mechanisms are poorly understood and important players are lacking. Here, we discovered a Rab5 effector, the five-subunit endosomal Rab5 and RNA/ribosome intermediary (FERRY) complex, that recruits mRNAs and ribosomes to early endosomes through direct mRNA-interaction. FERRY displays preferential binding to certain groups of transcripts, including mRNAs encoding mitochondrial proteins. Deletion of FERRY subunits reduces the endosomal localization of transcripts in cells and has a significant impact on mRNA levels. Clinical studies show that genetic disruption of FERRY causes severe brain damage. We found that, in neurons, FERRY co-localizes with mRNA on early endosomes, and mRNA loaded FERRY-positive endosomes are in close proximity of mitochondria. FERRY thus transforms endosomes into mRNA carriers and plays a key role in regulating mRNA distribution and transport.
Topics: rab5 GTP-Binding Proteins; RNA, Messenger; Endosomes; Biological Transport; Endocytosis
PubMed: 37267905
DOI: 10.1016/j.molcel.2023.05.012 -
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 -
The EMBO Journal Sep 2022Macrophage polarization is a process whereby macrophages acquire distinct effector states (M1 or M2) to carry out multiple and sometimes opposite functions. We show here...
Macrophage polarization is a process whereby macrophages acquire distinct effector states (M1 or M2) to carry out multiple and sometimes opposite functions. We show here that translational reprogramming occurs during macrophage polarization and that this relies on the Elongator complex subunit Elp3, an enzyme that modifies the wobble uridine base U34 in cytosolic tRNAs. Elp3 expression is downregulated by classical M1-activating signals in myeloid cells, where it limits the production of pro-inflammatory cytokines via FoxO1 phosphorylation, and attenuates experimental colitis in mice. In contrast, alternative M2-activating signals upregulate Elp3 expression through a PI3K- and STAT6-dependent signaling pathway. The metabolic reprogramming linked to M2 macrophage polarization relies on Elp3 and the translation of multiple candidates, including the mitochondrial ribosome large subunit proteins Mrpl3, Mrpl13, and Mrpl47. By promoting translation of its activator Ric8b in a codon-dependent manner, Elp3 also regulates mTORC2 activation. Elp3 expression in myeloid cells further promotes Wnt-driven tumor initiation in the intestine by maintaining a pool of tumor-associated macrophages exhibiting M2 features. Collectively, our data establish a functional link between tRNA modifications, mTORC2 activation, and macrophage polarization.
Topics: Animals; Codon; Histone Acetyltransferases; Macrophage Activation; Macrophages; Mechanistic Target of Rapamycin Complex 2; Mice; Signal Transduction
PubMed: 35920020
DOI: 10.15252/embj.2021109353