-
Molecular Cell Mar 2023Biogenesis of mitochondria requires the import of approximately 1,000 different precursor proteins into and across the mitochondrial membranes. Mitochondria exhibit a... (Review)
Review
Biogenesis of mitochondria requires the import of approximately 1,000 different precursor proteins into and across the mitochondrial membranes. Mitochondria exhibit a wide variety of mechanisms and machineries for the translocation and sorting of precursor proteins. Five major import pathways that transport proteins to their functional intramitochondrial destination have been elucidated; these pathways range from the classical amino-terminal presequence-directed pathway to pathways using internal or even carboxy-terminal targeting signals in the precursors. Recent studies have provided important insights into the structural organization of membrane-embedded preprotein translocases of mitochondria. A comparison of the different translocases reveals the existence of at least three fundamentally different mechanisms: two-pore-translocase, β-barrel switching, and transport cavities open to the lipid bilayer. In addition, translocases are physically engaged in dynamic interactions with respiratory chain complexes, metabolite transporters, quality control factors, and machineries controlling membrane morphology. Thus, mitochondrial preprotein translocases are integrated into multi-functional networks of mitochondrial and cellular machineries.
Topics: Mitochondrial Proteins; Mitochondria; Mitochondrial Membranes; Carrier Proteins; Protein Transport; Protein Precursors; Mitochondrial Membrane Transport Proteins
PubMed: 36931257
DOI: 10.1016/j.molcel.2023.02.020 -
Neuroscience Research Dec 2023The past 20 years of research on axon degeneration has revealed fine details on how NAD biology controls axonal survival. Extensive data demonstrate that the NAD... (Review)
Review
The past 20 years of research on axon degeneration has revealed fine details on how NAD biology controls axonal survival. Extensive data demonstrate that the NAD precursor NMN binds to and activates the pro-degenerative enzyme SARM1, so a failure to convert sufficient NMN into NAD leads to toxic NMN accumulation and axon degeneration. This involvement of NMN brings the axon degeneration field to an unexpected overlap with research into ageing and extending healthy lifespan. A decline in NAD levels throughout life, at least in some tissues, is believed to contribute to age-related functional decay and boosting NAD production with supplementation of NMN or other NAD precursors has gained attention as a potential anti-ageing therapy. Recent years have witnessed an influx of NMN-based products and related molecules on the market, sold as food supplements, with many people taking these supplements daily. While several clinical trials are ongoing to check the safety profiles and efficacy of NAD precursors, sufficient data to back their therapeutic use are still lacking. Here, we discuss NMN supplementation, SARM1 and anti-ageing strategies, with an important question in mind: considering that NMN accumulation can lead to axon degeneration, how is this compatible with its beneficial effect in ageing and are there circumstances in which NMN supplementation could become harmful?
Topics: Humans; NAD; Axons; Aging
PubMed: 36657725
DOI: 10.1016/j.neures.2023.01.004 -
International Journal of Molecular... Dec 2021Thousands of naturally occurring peptides differing in their origin, abundance and possible functions have been identified in the tissue and biological fluids of... (Review)
Review
Thousands of naturally occurring peptides differing in their origin, abundance and possible functions have been identified in the tissue and biological fluids of vertebrates, insects, fungi, plants and bacteria. These peptide pools are referred to as intracellular or extracellular peptidomes, and besides a small proportion of well-characterized peptide hormones and defense peptides, are poorly characterized. However, a growing body of evidence suggests that unknown bioactive peptides are hidden in the peptidomes of different organisms. In this review, we present a comprehensive overview of the mechanisms of generation and properties of peptidomes across different organisms. Based on their origin, we propose three large peptide groups-functional protein "degradome", small open reading frame (smORF)-encoded peptides (smORFome) and specific precursor-derived peptides. The composition of peptide pools identified by mass-spectrometry analysis in human cells, plants, yeast and bacteria is compared and discussed. The functions of different peptide groups, for example the role of the "degradome" in promoting defense signaling, are also considered.
Topics: Bacterial Proteins; Fungal Proteins; Humans; Mass Spectrometry; Open Reading Frames; Peptides; Plant Proteins; Proteasome Endopeptidase Complex; Protein Precursors; Proteomics
PubMed: 34884929
DOI: 10.3390/ijms222313128 -
Nutrients Jul 2023Dietary vitamin B3 components, such as nicotinamide and nicotinic acid, are precursors to the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD). NAD... (Review)
Review
Dietary vitamin B3 components, such as nicotinamide and nicotinic acid, are precursors to the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD). NAD levels are thought to decline with age and disease. While the drivers of this decline remain under intense investigation, strategies have emerged seeking to functionally maintain NAD levels through supplementation with NAD biosynthetic intermediates. These include marketed products, such as nicotinamide riboside (NR) and its phosphorylated form (NMN). More recent developments have shown that NRH (the reduced form of NR) and its phosphorylated form NMNH also increases NAD levels upon administration, although they initially generate NADH (the reduced form of NAD). Other means to increase the combined levels of NAD and NADH, NAD(H), include the inhibition of NAD-consuming enzymes or activation of biosynthetic pathways. Multiple studies have shown that supplementation with an NAD(H) precursor changes the profile of NAD(H) catabolism. Yet, the pharmacological significance of NAD(H) catabolites is rarely considered although the distribution and abundance of these catabolites differ depending on the NAD(H) precursor used, the species in which the study is conducted, and the tissues used for the quantification. Significantly, some of these metabolites have emerged as biomarkers in physiological disorders and might not be innocuous. Herein, we review the known and emerging catabolites of the NAD(H) metabolome and highlight their biochemical and physiological function as well as key chemical and biochemical reactions leading to their formation. Furthermore, we emphasize the need for analytical methods that inform on the full NAD(H) metabolome since the relative abundance of NAD(H) catabolites informs how NAD(H) precursors are used, recycled, and eliminated.
Topics: NAD; Niacinamide; Niacin; Metabolome; Oxidation-Reduction; Biomarkers
PubMed: 37447389
DOI: 10.3390/nu15133064 -
International Journal of Molecular... Dec 2022Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to... (Review)
Review
Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to the misfolding and accumulation of a specific protein. Amyloid deposits can be found in several organs, including the heart, brain, kidneys, and spleen, and can affect single or multiple organs. Generally, amyloid-forming proteins become prone to aggregate due to genetic mutations, acquired environmental factors, excessive concentration, or post-translational modifications. Interestingly, amyloid aggregates are often composed of proteolytic fragments, derived from the degradation of precursor proteins by yet unidentified proteases, which display higher amyloidogenic tendency compared to precursor proteins, thus representing an important mechanism in the onset of amyloid-based diseases. In the present review, we summarize the current knowledge on the proteolytic susceptibility of three of the main human amyloidogenic proteins, i.e., transthyretin, β-amyloid precursor protein, and α-synuclein, in the onset of amyloidosis. We also highlight the role that proteolytic enzymes can play in the crosstalk between intestinal inflammation and amyloid-based diseases.
Topics: Humans; Proteolysis; Amyloidosis; Amyloid; Amyloid beta-Protein Precursor; Protein Precursors; Prealbumin; Peptide Hydrolases
PubMed: 36614141
DOI: 10.3390/ijms24010699 -
The FEBS Journal Jul 2022Coordination of transcription and processing of RNA is a basic principle in regulation of gene expression in eukaryotes. In the case of mRNA, coordination is primarily... (Review)
Review
Coordination of transcription and processing of RNA is a basic principle in regulation of gene expression in eukaryotes. In the case of mRNA, coordination is primarily founded on a co-transcriptional processing mechanism by which a nascent precursor mRNA undergoes maturation via cleavage and modification by the transcription machinery. A similar mechanism controls the biosynthesis of rRNA. However, the coordination of transcription and processing of tRNA, a rather short transcript, remains unknown. Here, we present a model for high molecular weight initiation complexes of human RNA polymerase III that assemble on tRNA genes and process precursor transcripts to mature forms. These multifunctional initiation complexes may support co-transcriptional processing, such as the removal of the 5' leader of precursor tRNA by RNase P. Based on this model, maturation of tRNA is predetermined prior to transcription initiation.
Topics: Humans; RNA Polymerase III; RNA Precursors; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA, Transfer; Ribonuclease P; Transcription, Genetic
PubMed: 33929081
DOI: 10.1111/febs.15904 -
Biomolecules Jul 2020Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize... (Review)
Review
Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize the majority of the cellular ATP. Like almost all mitochondrial proteins, carriers have to be imported into mitochondria from the cytosol. Carrier precursors utilize a specialized translocation pathway dedicated to the biogenesis of carriers and related proteins, the carrier translocase of the inner membrane (TIM22) pathway. After recognition and import through the mitochondrial outer membrane via the translocase of the outer membrane (TOM) complex, carrier precursors are ushered through the intermembrane space by hexameric TIM chaperones and ultimately integrated into the inner membrane by the TIM22 carrier translocase. Recent advances have shed light on the mechanisms of TOM translocase and TIM chaperone function, uncovered an unexpected versatility of the machineries, and revealed novel components and functional crosstalk of the human TIM22 translocase.
Topics: Biological Transport; Carrier Proteins; Humans; Membrane Transport Proteins; Mitochondria; Mitochondrial Membranes; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Signal Transduction
PubMed: 32645990
DOI: 10.3390/biom10071008 -
The FEBS Journal Nov 2022Most chloroplast proteins are nucleus-encoded, translated on cytoplasmic ribosomes as precursor proteins, and imported into chloroplasts through TOC and TIC, the... (Review)
Review
Most chloroplast proteins are nucleus-encoded, translated on cytoplasmic ribosomes as precursor proteins, and imported into chloroplasts through TOC and TIC, the translocons of the outer and inner chloroplast envelope membranes. While the composition of the TOC complex is well established, there is still some controversy about the importance of a recently identified TIC complex consisting of Tic20, Tic214, Tic100, and Tic56. TOC and TIC form a supercomplex with a protein channel at the junction of the outer and inner envelope membranes through which preproteins are pulled into the stroma by the ATP-powered Ycf2 complex consisting of several FtsH-like ATPases and/or by chloroplast Hsp proteins. Several components of the TOC/TIC system are moonlighting proteins with additional roles in chloroplast gene expression and metabolism. Chaperones and co-chaperones, associated with TOC and TIC on the cytoplasmic and stromal side of the chloroplast envelope, participate in the unfolding and folding of the precursor proteins and act together with the ubiquitin-proteasome system in protein quality control. Chloroplast protein import is also intimately linked with retrograde signaling, revealing altogether an unsuspected complexity in the regulation of this process.
Topics: Plant Proteins; Chloroplasts; Chloroplast Proteins; Protein Transport; Molecular Chaperones; Protein Precursors
PubMed: 35472255
DOI: 10.1111/febs.16464 -
Frontiers in Endocrinology 2020Maintenance of adipocyte precursors is critical for regulating metabolism and preventing obesity related disease. These precursors have been immortalized and studied in... (Review)
Review
Maintenance of adipocyte precursors is critical for regulating metabolism and preventing obesity related disease. These precursors have been immortalized and studied in cellular models as well as-more recently-in animal models. However, little is known about adipocyte precursors from animals of different ages. Most research has focused on adipocyte precursors during obesity. This review goes over the most recent reports of adipocyte precursors during development and in adulthood. Some of these new analyses are due to new techniques such as single cell-RNA sequencing and temporally controlled lineage tracing. With these tools, we have been able to further our understanding of adipocyte precursor lineages and their different regulatory mechanisms. As we learn more about adipocyte precursor plasticity and regulation, we can hope to use this knowledge for future clinical applications.
Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Cell Differentiation; Humans; Obesity; Single-Cell Analysis
PubMed: 33679601
DOI: 10.3389/fendo.2020.613606 -
BioRxiv : the Preprint Server For... Apr 2023The appropriate development of macrophages, the body's professional phagocyte, is essential for organismal development, especially in mammals. This dependence is...
UNLABELLED
The appropriate development of macrophages, the body's professional phagocyte, is essential for organismal development, especially in mammals. This dependence is exemplified by the observation that loss-of-function mutations in colony stimulating factor 1 receptor (CSF1R) results in multiple tissue abnormalities owing to an absence of macrophages. Despite this importance, little is known about the molecular and cell biological regulation of macrophage development. Here, we report the surprising finding that the chloride-sensing kinase With-no-lysine 1 (WNK1) is required for development of tissue-resident macrophages (TRMs). Myeloid-specific deletion of resulted in a dramatic loss of TRMs, disrupted organ development, systemic neutrophilia, and mortality between 3 and 4 weeks of age. Strikingly, we found that myeloid progenitors or precursors lacking WNK1 not only failed to differentiate into macrophages, but instead differentiated into neutrophils. Mechanistically, the cognate CSF1R cytokine macrophage-colony stimulating factor (M-CSF) stimulates macropinocytosis by both mouse and human myeloid progenitors and precursor cells. Macropinocytosis, in turn, induces chloride flux and WNK1 phosphorylation. Importantly, blocking macropinocytosis, perturbing chloride flux during macropinocytosis, and inhibiting WNK1 chloride-sensing activity each skewed myeloid progenitor differentiation from macrophages into neutrophils. Thus, we have elucidated a role for WNK1 during macropinocytosis and discovered a novel function of macropinocytosis in myeloid progenitors and precursor cells to ensure macrophage lineage fidelity.
HIGHLIGHTS
Myeloid-specific WNK1 loss causes failed macrophage development and premature deathM-CSF-stimulated myeloid progenitors and precursors become neutrophils instead of macrophagesM-CSF induces macropinocytosis by myeloid progenitors, which depends on WNK1Macropinocytosis enforces macrophage lineage commitment.
PubMed: 37383948
DOI: 10.1101/2023.04.26.538482