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Annual Review of Biochemistry Jun 2018Clathrin-mediated endocytosis (CME) is the major endocytic pathway in mammalian cells. It is responsible for the uptake of transmembrane receptors and transporters, for... (Review)
Review
Clathrin-mediated endocytosis (CME) is the major endocytic pathway in mammalian cells. It is responsible for the uptake of transmembrane receptors and transporters, for remodeling plasma membrane composition in response to environmental changes, and for regulating cell surface signaling. CME occurs via the assembly and maturation of clathrin-coated pits that concentrate cargo as they invaginate and pinch off to form clathrin-coated vesicles. In addition to the major coat proteins, clathrin triskelia and adaptor protein complexes, CME requires a myriad of endocytic accessory proteins and phosphatidylinositol lipids. CME is regulated at multiple steps-initiation, cargo selection, maturation, and fission-and is monitored by an endocytic checkpoint that induces disassembly of defective pits. Regulation occurs via posttranslational modifications, allosteric conformational changes, and isoform and splice-variant differences among components of the CME machinery, including the GTPase dynamin. This review summarizes recent findings on the regulation of CME and the evolution of this complex process.
Topics: Adaptor Protein Complex 2; Allosteric Regulation; Animals; Clathrin; Clathrin-Coated Vesicles; Dynamins; Endocytosis; Evolution, Molecular; Humans; Models, Biological; Phosphatidylinositol Phosphates; Phosphorylation; Protein Conformation; Signal Transduction
PubMed: 29661000
DOI: 10.1146/annurev-biochem-062917-012644 -
Acta Pharmacologica Sinica May 2021Mitochondria are highly dynamic organelles undergoing cycles of fusion and fission to modulate their morphology, distribution, and function, which are referred as... (Review)
Review
Mitochondria are highly dynamic organelles undergoing cycles of fusion and fission to modulate their morphology, distribution, and function, which are referred as 'mitochondrial dynamics'. Dynamin-related protein 1 (Drp1) is known as the major pro-fission protein whose activity is tightly regulated to clear the damaged mitochondria via mitophagy, ensuring a strict control over the intricate process of cellular and organ dynamics in heart. Various posttranslational modifications (PTMs) of Drp1 have been identified including phosphorylation, SUMOylation, palmitoylation, ubiquitination, S-nitrosylation, and O-GlcNAcylation, which implicate a role in the regulation of mitochondrial dynamics. An intact mitochondrial homeostasis is critical for heart to fuel contractile function and cardiomyocyte metabolism, while defects in mitochondrial dynamics constitute an essential part of the pathophysiology underlying various cardiovascular diseases (CVDs). In this review, we summarize current knowledge on the critical role of Drp1 in the pathogenesis of CVDs including endothelial dysfunction, smooth muscle remodeling, cardiac hypertrophy, pulmonary arterial hypertension, myocardial ischemia-reperfusion, and myocardial infarction. We also highlight how the targeting of Drp1 could potentially contribute to CVDs treatments.
Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Dynamins; Enzyme Inhibitors; Humans; Mitochondria; Mitochondrial Dynamics; Protein Processing, Post-Translational; Vascular Remodeling
PubMed: 32913266
DOI: 10.1038/s41401-020-00518-y -
Trends in Cell Biology Jan 2021Mitochondria are highly dynamic organelles that constantly undergo fission and fusion. Disruption of mitochondrial dynamics undermines their function and causes several... (Review)
Review
Mitochondria are highly dynamic organelles that constantly undergo fission and fusion. Disruption of mitochondrial dynamics undermines their function and causes several human diseases. The fusion of the outer (OMM) and inner mitochondrial membranes (IMM) is mediated by two classes of dynamin-like protein (DLP): mitofusin (MFN)/fuzzy onions 1 (Fzo1) and optic atrophy 1/mitochondria genome maintenance 1 (OPA1/Mgm1). Given the lack of structural information on these fusogens, the molecular mechanisms underlying mitochondrial fusion remain unclear, even after 20 years. Here, we review recent advances in structural studies of the mitochondrial fusion machinery, discuss their implication for DLPs, and summarize the pathogenic mechanisms of disease-causing mutations in mitochondrial fusion DLPs.
Topics: Dynamins; Humans; Membrane Fusion; Mitochondrial Dynamics; Mitochondrial Membranes; Mitochondrial Proteins; Structural Homology, Protein
PubMed: 33092941
DOI: 10.1016/j.tcb.2020.09.008 -
Nature Reviews. Cardiology Nov 2022Mitochondria are organelles involved in the regulation of various important cellular processes, ranging from ATP generation to immune activation. A healthy mitochondrial... (Review)
Review
Mitochondria are organelles involved in the regulation of various important cellular processes, ranging from ATP generation to immune activation. A healthy mitochondrial network is essential for cardiovascular function and adaptation to pathological stressors. Mitochondria undergo fission or fusion in response to various environmental cues, and these dynamic changes are vital for mitochondrial function and health. In particular, mitochondrial fission is closely coordinated with the cell cycle and is linked to changes in mitochondrial respiration and membrane permeability. Another key function of fission is the segregation of damaged mitochondrial components for degradation by mitochondrial autophagy (mitophagy). Mitochondrial fission is induced by the large GTPase dynamin-related protein 1 (DRP1) and is subject to sophisticated regulation. Activation requires various post-translational modifications of DRP1, actin polymerization and the involvement of other organelles such as the endoplasmic reticulum, Golgi apparatus and lysosomes. A decrease in mitochondrial fusion can also shift the balance towards mitochondrial fission. Although mitochondrial fission is necessary for cellular homeostasis, this process is often aberrantly activated in cardiovascular disease. Indeed, strong evidence exists that abnormal mitochondrial fission directly contributes to disease development. In this Review, we compare the physiological and pathophysiological roles of mitochondrial fission and discuss the therapeutic potential of preventing excessive mitochondrial fission in the heart and vasculature.
Topics: Actins; Adenosine Triphosphate; Dynamins; GTP Phosphohydrolases; Humans; Mitochondrial Dynamics
PubMed: 35523864
DOI: 10.1038/s41569-022-00703-y -
Nature Feb 2021Mitochondria form dynamic networks in the cell that are balanced by the flux of iterative fusion and fission events of the organelles. It is now appreciated that... (Review)
Review
Mitochondria form dynamic networks in the cell that are balanced by the flux of iterative fusion and fission events of the organelles. It is now appreciated that mitochondrial fission also represents an end-point event in a signalling axis that allows cells to sense and respond to external cues. The fission process is orchestrated by membrane-associated adaptors, influenced by organellar and cytoskeletal interactions and ultimately executed by the dynamin-like GTPase DRP1. Here we invoke the framework of the 'mitochondrial divisome', which is conceptually and operationally similar to the bacterial cell-division machinery. We review the functional and regulatory aspects of the mitochondrial divisome and, within this framework, parse the core from the accessory machinery. In so doing, we transition from a phenomenological to a mechanistic understanding of the fission process.
Topics: Animals; Biological Evolution; Calcium Signaling; Cell Death; Disease; Dynamins; Health; Humans; Mitochondria; Mitochondrial Dynamics
PubMed: 33536648
DOI: 10.1038/s41586-021-03214-x -
Redox Biology Jun 2023Glaucoma is a common neurodegenerative disease characterized by progressive retinal ganglion cell (RGC) loss and visual field defects. Pathologically high intraocular...
Glaucoma is a common neurodegenerative disease characterized by progressive retinal ganglion cell (RGC) loss and visual field defects. Pathologically high intraocular pressure (ph-IOP) is an important risk factor for glaucoma, and it triggers molecularly distinct cascades that control RGC death and axonal degeneration. Dynamin-related protein 1 (Drp1)-mediated abnormalities in mitochondrial dynamics are involved in glaucoma pathogenesis; however, little is known about the precise pathways that regulate RGC injury and death. Here, we aimed to investigate the role of the ERK1/2-Drp1-reactive oxygen species (ROS) axis in RGC death and the relationship between Drp1-mediated mitochondrial dynamics and PANoptosis in ph-IOP injury. Our results suggest that inhibiting the ERK1/2-Drp1-ROS pathway is a potential therapeutic strategy for treating ph-IOP-induced injuries. Furthermore, inhibiting Drp1 can regulate RGC PANoptosis by modulating caspase3-dependent, nucleotide-binding oligomerization domain-like receptor-containing pyrin domain 3(NLRP3)-dependent, and receptor-interacting protein (RIP)-dependent pathways in the ph-IOP model. Overall, our findings provide new insights into possible protective interventions that could regulate mitochondrial dynamics to improve RGC survival.
Topics: Humans; Animals; Retinal Ganglion Cells; Intraocular Pressure; Neurodegenerative Diseases; Reactive Oxygen Species; Glaucoma; Dynamins; Mitochondria; Disease Models, Animal
PubMed: 36989574
DOI: 10.1016/j.redox.2023.102687 -
Journal of Molecular and Cellular... May 2020Maintenance of mitochondrial function and integrity is critical for normal cell survival, particularly in non-dividing cells with a high-energy demand such as... (Review)
Review
Maintenance of mitochondrial function and integrity is critical for normal cell survival, particularly in non-dividing cells with a high-energy demand such as cardiomyocytes. Well-coordinated quality control mechanisms in cardiomyocytes, involving mitochondrial biogenesis, mitochondrial dynamics-fission and fusion, and mitophagy, act to protect against mitochondrial dysfunction. Mitochondrial fission, which requires dynamin-related protein 1 (Drp1), is essential for segregation of damaged mitochondria for degradation. Alterations in this process have been linked to cardiomyocyte apoptosis and cardiomyopathy. In this review, we discuss the role of Drp1 in mitophagy and apoptosis in the context of cardiac pathology, including myocardial ischemia and heart failure.
Topics: Animals; Apoptosis; Cardiomyopathies; Cell Death; Disease Susceptibility; Dynamins; Gene Expression Regulation; Humans; Mitochondria, Heart; Mitochondrial Dynamics; Mitophagy; Myocytes, Cardiac; Necroptosis; Protein Processing, Post-Translational; Signal Transduction
PubMed: 32302592
DOI: 10.1016/j.yjmcc.2020.04.015 -
Nature Communications May 2020Mitochondria undergo dynamic fusion/fission, biogenesis and mitophagy in response to stimuli or stresses. Disruption of mitochondrial homeostasis could lead to cell...
Mitochondria undergo dynamic fusion/fission, biogenesis and mitophagy in response to stimuli or stresses. Disruption of mitochondrial homeostasis could lead to cell senescence, although the underlying mechanism remains unclear. We show that deletion of mitochondrial phosphatase PGAM5 leads to accelerated retinal pigment epithelial (RPE) senescence in vitro and in vivo. Mechanistically, PGAM5 is required for mitochondrial fission through dephosphorylating DRP1. PGAM5 deletion leads to increased mitochondrial fusion and decreased mitochondrial turnover. As results, cellular ATP and reactive oxygen species (ROS) levels are elevated, mTOR and IRF/IFN-β signaling pathways are enhanced, leading to cellular senescence. Overexpression of Drp1 K38A or S637A mutant phenocopies or rescues mTOR activation and senescence in PGAM5 cells, respectively. Young but not aging Pgam5 mice are resistant to sodium iodate-induced RPE cell death. Our studies establish a link between defective mitochondrial fission, cellular senescence and age-dependent oxidative stress response, which have implications in age-related diseases.
Topics: Age Factors; Animals; Cell Line; Cellular Senescence; Dynamins; Gene Expression Regulation; Humans; Mice; Mice, Knockout; Mitochondria; Mitochondrial Dynamics; Oxidative Stress; Phosphoprotein Phosphatases; Retinal Pigment Epithelium; Signal Transduction
PubMed: 32439975
DOI: 10.1038/s41467-020-16312-7 -
Nature Metabolism Dec 2023Neurons are particularly susceptible to energy fluctuations in response to stress. Mitochondrial fission is highly regulated to generate ATP via oxidative...
Neurons are particularly susceptible to energy fluctuations in response to stress. Mitochondrial fission is highly regulated to generate ATP via oxidative phosphorylation; however, the role of a regulator of mitochondrial fission in neuronal energy metabolism and synaptic efficacy under chronic stress remains elusive. Here, we show that chronic stress promotes mitochondrial fission in the medial prefrontal cortex via activating dynamin-related protein 1 (Drp1), resulting in mitochondrial dysfunction in male mice. Both pharmacological inhibition and genetic reduction of Drp1 ameliorates the deficit of excitatory synaptic transmission and stress-related depressive-like behavior. In addition, enhancing Drp1 fission promotes stress susceptibility, which is alleviated by coenzyme Q10, which potentiates mitochondrial ATP production. Together, our findings unmask the role of Drp1-dependent mitochondrial fission in the deficits of neuronal metabolic burden and depressive-like behavior and provides medication basis for metabolism-related emotional disorders.
Topics: Mice; Male; Animals; Mitochondrial Dynamics; Dynamins; Neurons; Mitochondria; Phosphorylation; Adenosine Triphosphate
PubMed: 37985735
DOI: 10.1038/s42255-023-00924-6 -
Molecular Cell Jun 2023Mitophagy plays an important role in mitochondrial homeostasis by selective degradation of mitochondria. During mitophagy, mitochondria should be fragmented to allow...
Mitophagy plays an important role in mitochondrial homeostasis by selective degradation of mitochondria. During mitophagy, mitochondria should be fragmented to allow engulfment within autophagosomes, whose capacity is exceeded by the typical mitochondria mass. However, the known mitochondrial fission factors, dynamin-related proteins Dnm1 in yeasts and DNM1L/Drp1 in mammals, are dispensable for mitophagy. Here, we identify Atg44 as a mitochondrial fission factor that is essential for mitophagy in yeasts, and we therefore term Atg44 and its orthologous proteins mitofissin. In mitofissin-deficient cells, a part of the mitochondria is recognized by the mitophagy machinery as cargo but cannot be enwrapped by the autophagosome precursor, the phagophore, due to a lack of mitochondrial fission. Furthermore, we show that mitofissin directly binds to lipid membranes and brings about lipid membrane fragility to facilitate membrane fission. Taken together, we propose that mitofissin acts directly on lipid membranes to drive mitochondrial fission required for mitophagy.
Topics: Animals; Mitophagy; Autophagy; Mitochondrial Dynamics; Mitochondrial Proteins; Mitochondria; Dynamins; Lipids; Mammals
PubMed: 37192628
DOI: 10.1016/j.molcel.2023.04.022