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Blood Advances Jul 2023Cell polarity, the asymmetric distribution of proteins and organelles, is permanently or transiently established in various cell types and plays an important role in...
Cell polarity, the asymmetric distribution of proteins and organelles, is permanently or transiently established in various cell types and plays an important role in many physiological events. epidermal growth factor receptor substrate 15 homology domain-binding protein 1-like 1 (EHBP1L1) is an adapter protein that is localized on recycling endosomes and regulates apical-directed transport in polarized epithelial cells. However, the role of EHBP1L1 in nonepithelial cells, remains unknown. Here, Ehbp1l1-/- mice showed impaired erythroblast enucleation. Further analyses showed that nuclear polarization before enucleation was impaired in Ehbp1l1-/- erythroblasts. It was also revealed that EHBP1L1 interactors Rab10, Bin1, and dynamin were involved in erythroblast enucleation. In addition, Ehbp1l1-/- erythrocytes exhibited stomatocytic morphology and dehydration. These defects in erythroid cells culminated in early postnatal anemic lethality in Ehbp1l1-/- mice. Moreover, we found the mislocalization of nuclei and mitochondria in the skeletal muscle cells of Ehbp1l1-/- mice, as observed in patients with centronuclear myopathy with genetic mutations in Bin1 or dynamin 2. Taken together, our findings indicate that the Rab8/10-EHBP1L1-Bin1-dynamin axis plays an important role in multiple cell polarity systems in epithelial and nonepithelial cells.
Topics: Animals; Mice; Adaptor Proteins, Signal Transducing; Cell Nucleus; Dynamins; Erythroblasts; Erythrocytes
PubMed: 37042948
DOI: 10.1182/bloodadvances.2022008930 -
International Journal of Molecular... Jul 2020Mitochondria and peroxisomes are ubiquitous subcellular organelles that are highly dynamic and possess a high degree of plasticity. These organelles proliferate through... (Review)
Review
Mitochondria and peroxisomes are ubiquitous subcellular organelles that are highly dynamic and possess a high degree of plasticity. These organelles proliferate through division of pre-existing organelles. Studies on yeast, mammalian cells, and unicellular algae have led to a surprising finding that mitochondria and peroxisomes share the components of their division machineries. At the heart of the mitochondrial and peroxisomal division machineries is a GTPase dynamin-like protein, Dnm1/Drp1, which forms a contractile ring around the neck of the dividing organelles. During division, Dnm1/Drp1 functions as a motor protein and constricts the membrane. This mechanochemical work is achieved by utilizing energy from GTP hydrolysis. Over the last two decades, studies have focused on the structure and assembly of Dnm1/Drp1 molecules around the neck. However, the regulation of GTP during the division of mitochondrion and peroxisome is not well understood. Here, we review the current understanding of Dnm1/Drp1-mediated divisions of mitochondria and peroxisomes, exploring the mechanisms of GTP regulation during the Dnm1/Drp1 function, and provide new perspectives on their potential contribution to mitochondrial and peroxisomal biogenesis.
Topics: Animals; Cell Division; Dynamins; GTP Phosphohydrolases; Humans; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Molecular Motor Proteins; Peroxisomes; Saccharomyces cerevisiae Proteins
PubMed: 32751702
DOI: 10.3390/ijms21155452 -
Frontiers in Endocrinology 2020Mitochondria are highly dynamic organelles and important for a variety of cellular functions. They constantly undergo fission and fusion events, referred to as... (Review)
Review
Mitochondria are highly dynamic organelles and important for a variety of cellular functions. They constantly undergo fission and fusion events, referred to as mitochondrial dynamics, which affects the shape, size, and number of mitochondria in the cell, as well as mitochondrial subcellular transport, mitochondrial quality control (mitophagy), and programmed cell death (apoptosis). Dysfunctional mitochondrial dynamics is associated with various human diseases. Mitochondrial dynamics is mediated by a set of mitochondria-shaping proteins in both yeast and mammals. In this review, we describe recent insights into the potential molecular mechanisms underlying mitochondrial fusion and fission, particularly highlighting the coordinating roles of different mitochondria-shaping proteins in the processes, as well as the roles of the endoplasmic reticulum (ER), the actin cytoskeleton and membrane phospholipids in the regulation of mitochondrial dynamics. We particularly focus on emerging roles for the mammalian mitochondrial proteins Fis1, Mff, and MIEFs (MIEF1 and MIEF2) in regulating the recruitment of the cytosolic Drp1 to the surface of mitochondria and how these proteins, especially Fis1, mediate crosstalk between the mitochondrial fission and fusion machineries. In summary, this review provides novel insights into the molecular mechanisms of mammalian mitochondrial dynamics and the involvement of these mechanisms in apoptosis and autophagy.
Topics: Animals; Dynamins; Humans; Membrane Proteins; Mitochondrial Dynamics; Mitochondrial Proteins; Mitophagy; Peptide Elongation Factors
PubMed: 32595603
DOI: 10.3389/fendo.2020.00374 -
Current Oncology Reports Dec 2022This study is aimed at reviewing the recent progress in Drp1 inhibition as a novel approach for reducing doxorubicin-induced cardiotoxicity and for improving cancer... (Review)
Review
PURPOSE OF REVIEW
This study is aimed at reviewing the recent progress in Drp1 inhibition as a novel approach for reducing doxorubicin-induced cardiotoxicity and for improving cancer treatment.
RECENT FINDINGS
Anthracyclines (e.g. doxorubicin) are one of the most common and effective chemotherapeutic agents to treat a variety of cancers. However, the clinical usage of doxorubicin has been hampered by its severe cardiotoxic side effects leading to heart failure. Mitochondrial dysfunction is one of the major aetiologies of doxorubicin-induced cardiotoxicity. The morphology of mitochondria is highly dynamic, governed by two opposing processes known as fusion and fission, collectively known as mitochondrial dynamics. An imbalance in mitochondrial dynamics is often reported in tumourigenesis which can lead to adaptive and acquired resistance to chemotherapy. Drp1 is a key mitochondrial fission regulator, and emerging evidence has demonstrated that Drp1-mediated mitochondrial fission is upregulated in both cancer cells to their survival advantage and injured heart tissue in the setting of doxorubicin-induced cardiotoxicity. Effective treatment to prevent and mitigate doxorubicin-induced cardiotoxicity is currently not available. Recent advances in cardio-oncology have highlighted that Drp1 inhibition holds great potential as a targeted mitochondrial therapy for doxorubicin-induced cardiotoxicity.
Topics: Humans; Mitochondrial Proteins; Cardiotoxicity; Dynamins; Mitochondria; Doxorubicin; Neoplasms
PubMed: 36181612
DOI: 10.1007/s11912-022-01333-w -
The Journal of Cell Biology Oct 2023Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by a...
Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by a dynamin-related protein, Dnm1 (Drp1 in humans), that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity is sufficient to complete the fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1 (also named Atg44). Loss of Mdi1 causes mitochondrial hyperfusion due to defects in fission, but not the lack of Dnm1 recruitment to mitochondria. Mdi1 is conserved in fungal species, and its homologs contain an amphipathic α-helix, mutations of which disrupt mitochondrial morphology. One model is that Mdi1 distorts mitochondrial membranes to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of Mdi1 inside mitochondria.
Topics: Dynamins; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes; Mitochondrial Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; GTP Phosphohydrolases
PubMed: 37540145
DOI: 10.1083/jcb.202303147 -
Proceedings of the National Academy of... Mar 2022The mechanoenzyme dynamin 2 (DNM2) is crucial for intracellular organization and trafficking. is mutated in dominant centronuclear myopathy (DNM2-CNM), a muscle disease...
The mechanoenzyme dynamin 2 (DNM2) is crucial for intracellular organization and trafficking. is mutated in dominant centronuclear myopathy (DNM2-CNM), a muscle disease characterized by defects in organelle positioning in myofibers. It remains unclear how the in vivo functions of DNM2 are regulated in muscle. Moreover, there is no therapy for DNM2-CNM to date. Here, we overexpressed human amphiphysin 2 (BIN1), a membrane remodeling protein mutated in other CNM forms, in and mice modeling mild and severe DNM2-CNM, through transgenesis or with adeno-associated virus (AAV). Increasing BIN1 improved muscle atrophy and main histopathological features of mice and rescued the perinatal lethality and survival of mice. In vitro experiments showed that BIN1 binds and recruits DNM2 to membrane tubules, and that the BIN1-DNM2 complex regulates tubules fission. Overall, BIN1 is a potential therapeutic target for dominant centronuclear myopathy linked to DNM2 mutations.
Topics: Adaptor Proteins, Signal Transducing; Animals; Dynamin II; Humans; Mice; Mice, Knockout; Muscular Atrophy; Muscular Diseases; Nuclear Proteins; Protein Binding; Tumor Suppressor Proteins
PubMed: 35217605
DOI: 10.1073/pnas.2109576119 -
Biochimica Et Biophysica Acta.... Nov 2022Mitochondria assemble in a highly dynamic network where interconnected tubules evolve in length and size through regulated cycles of fission and fusion of mitochondrial... (Review)
Review
Mitochondria assemble in a highly dynamic network where interconnected tubules evolve in length and size through regulated cycles of fission and fusion of mitochondrial membranes thereby adapting to cellular needs. Mitochondrial fusion and fission processes are mediated by specific sets of mechano-chemical large GTPases that belong to the Dynamin-Related Proteins (DRPs) super family. DRPs bind to cognate membranes and auto-oligomerize to drive lipid bilayers remodeling in a nucleotide dependent manner. Although structural characterization and mechanisms of DRPs that mediate membrane fission are well established, the capacity of DRPs to mediate membrane fusion is only emerging. In this review, we discuss the distinct structures and mechanisms of DRPs that trigger the anchoring and fusion of biological membranes with a specific focus on mitofusins that are dedicated to the fusion of mitochondrial outer membranes. In particular, we will highlight oligomeric assemblies of distinct DRPs and confront their mode of action against existing models of mitofusins assemblies with emphasis on recent biochemical, structural and computational reports. As we will see, the literature brings valuable insights into the presumed macro-assemblies mitofusins may form during anchoring and fusion of mitochondrial outer membranes.
Topics: Dynamins; GTP Phosphohydrolases; Lipid Bilayers; Membrane Fusion; Nucleotides
PubMed: 36057374
DOI: 10.1016/j.bbabio.2022.148913 -
Nature Communications Jan 2024The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial and peroxisomal fission, but the regulatory mechanisms remain ambiguous. Here we find...
The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial and peroxisomal fission, but the regulatory mechanisms remain ambiguous. Here we find that a conserved, intrinsically disordered, six-residue Short Linear Motif at the extreme Drp1 C-terminus, named CT-SLiM, constitutes a critical allosteric site that controls Drp1 structure and function in vitro and in vivo. Extension of the CT-SLiM by non-native residues, or its interaction with the protein partner GIPC-1, constrains Drp1 subunit conformational dynamics, alters self-assembly properties, and limits cooperative GTP hydrolysis, surprisingly leading to the fission of model membranes in vitro. In vivo, the involvement of the native CT-SLiM is critical for productive mitochondrial and peroxisomal fission, as both deletion and non-native extension of the CT-SLiM severely impair their progression. Thus, contrary to prevailing models, Drp1-catalyzed membrane fission relies on allosteric communication mediated by the CT-SLiM, deceleration of GTPase activity, and coupled changes in subunit architecture and assembly-disassembly dynamics.
Topics: Dynamins; GTP Phosphohydrolases; Mitochondria; Hydrolysis; Membrane Fusion; Mitochondrial Dynamics; Mitochondrial Proteins
PubMed: 38168038
DOI: 10.1038/s41467-023-44413-6 -
Arthritis Research & Therapy Jul 2023Gouty arthritis is the most frequently diagnosed inflammatory arthritis worldwide. Dynamin-related protein 1 (Drp1), a regulator of mitochondrial fission, contributes to...
BACKGROUND
Gouty arthritis is the most frequently diagnosed inflammatory arthritis worldwide. Dynamin-related protein 1 (Drp1), a regulator of mitochondrial fission, contributes to various inflammatory disorders via activating NLRP3 inflammasome. However, the biological role of Drp1 in gouty arthritis remains undefined.
METHODS
A mouse model of monosodium urate (MSU)-induced gouty arthritis and MSU-stimulated macrophages were established as in vivo and in vitro models, respectively. Histological changes were assessed by H&E and IHC analysis. RT-qPCR and western blot were used to detect the expression of Drp1 and the key molecules in joint tissues and macrophages. Cytokine secretion was measured by ELISA assay, and antioxidant enzymes activities and LDH release were monitored using commercial kits. Mitochondrial structure and functions were assessed by transmission electron microscopy (TEM) and MitoSOX staining. Co-IP and GST pull-down assay were used to detect the direct interaction between USP16 and Drp1, as well as the ubiquitination of Drp1.
RESULTS
Drp1 was elevated in MSU-induced gouty arthritis model, and it induced gouty arthritis via NF-κB pathway and NLRP3 inflammasome activation. In addition, Drp1 activated NF-κB/NLRP3 signaling via modulating mitochondrial fission. Mechanistically, USP16 mediated deubiquitination and stabilization of Drp1 through its direct interaction with Drp1. Functional studies further showed that USP16 was highly expressed in MSU-stimulated macrophages and induced gouty arthritis via Drp1-dependent NLRP3 inflammasome activation.
CONCLUSION
Deubiquitinase USP16 induced gouty arthritis via Drp1-dependent mitochondrial fission and NF-κB/NLRP3 signaling.
Topics: Animals; Mice; Arthritis, Gouty; NF-kappa B; Inflammasomes; Mitochondrial Dynamics; NLR Family, Pyrin Domain-Containing 3 Protein; Dynamins; Deubiquitinating Enzymes
PubMed: 37488647
DOI: 10.1186/s13075-023-03095-7 -
The Journal of Cell Biology Dec 2023Live super-resolution microscopy has allowed for new insights into recently identified mitochondria-lysosome contact sites, which mediate crosstalk between mitochondria...
Live super-resolution microscopy has allowed for new insights into recently identified mitochondria-lysosome contact sites, which mediate crosstalk between mitochondria and lysosomes, including co-regulation of Rab7 GTP hydrolysis and Drp1 GTP hydrolysis. Here, we highlight recent findings and future perspectives on this dynamic pathway and its roles in health and disease.
Topics: Guanosine Triphosphate; Lysosomes; Microscopy; Mitochondria; Mitochondrial Membranes; rab7 GTP-Binding Proteins; Dynamins
PubMed: 37917024
DOI: 10.1083/jcb.202305032