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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 -
Nature Cell Biology Dec 2021Mitochondrial-derived vesicles (MDVs) are implicated in diverse physiological processes-for example, mitochondrial quality control-and are linked to various...
Mitochondrial-derived vesicles (MDVs) are implicated in diverse physiological processes-for example, mitochondrial quality control-and are linked to various neurodegenerative diseases. However, their specific cargo composition and complex molecular biogenesis are still unknown. Here we report the proteome and lipidome of steady-state TOMM20 MDVs. We identified 107 high-confidence MDV cargoes, which include all β-barrel proteins and the TOM import complex. MDV cargoes are delivered as fully assembled complexes to lysosomes, thus representing a selective mitochondrial quality control mechanism for multi-subunit complexes, including the TOM machinery. Moreover, we define key biogenesis steps of phosphatidic acid-enriched MDVs starting with the MIRO1/2-dependent formation of thin membrane protrusions pulled along microtubule filaments, followed by MID49/MID51/MFF-dependent recruitment of the dynamin family GTPase DRP1 and finally DRP1-dependent scission. In summary, we define the function of MDVs in mitochondrial quality control and present a mechanistic model for global GTPase-driven MDV biogenesis.
Topics: Animals; COS Cells; Cell Line, Tumor; Chlorocebus aethiops; Cytoplasmic Vesicles; Dynamins; HEK293 Cells; HeLa Cells; Humans; Lipidomics; Membrane Proteins; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Neurodegenerative Diseases; Peptide Elongation Factors; Phosphatidic Acids; Proteome; RNA Interference; RNA, Small Interfering; rho GTP-Binding Proteins
PubMed: 34873283
DOI: 10.1038/s41556-021-00798-4 -
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 -
Nature Cell Biology May 2023Acute lysosomal membrane damage reduces the cellular population of functional lysosomes. However, these damaged lysosomes have a remarkable recovery potential...
Acute lysosomal membrane damage reduces the cellular population of functional lysosomes. However, these damaged lysosomes have a remarkable recovery potential independent of lysosomal biogenesis and remain unaffected in cells depleted in TFEB and TFE3. We combined proximity-labelling-based proteomics, biochemistry and high-resolution microscopy to unravel a lysosomal membrane regeneration pathway that depends on ATG8, the lysosomal membrane protein LIMP2, the RAB7 GTPase-activating protein TBC1D15 and proteins required for autophagic lysosomal reformation, including dynamin-2, kinesin-5B and clathrin. Following lysosomal damage, LIMP2 acts as a lysophagy receptor to bind ATG8, which in turn recruits TBC1D15 to damaged membranes. TBC1D15 interacts with ATG8 proteins on damaged lysosomes and provides a scaffold to assemble and stabilize the autophagic lysosomal reformation machinery. This potentiates the formation of lysosomal tubules and subsequent dynamin-2-dependent scission. TBC1D15-mediated lysosome regeneration was also observed in a cell culture model of oxalate nephropathy.
Topics: Dynamin II; Autophagy; Intracellular Membranes; GTPase-Activating Proteins; Lysosomes
PubMed: 37024685
DOI: 10.1038/s41556-023-01125-9 -
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 Cancer Jun 2023Disseminated tumor cells with metabolic flexibility to utilize available nutrients in distal organs persist, but the precise mechanisms that facilitate metabolic...
Disseminated tumor cells with metabolic flexibility to utilize available nutrients in distal organs persist, but the precise mechanisms that facilitate metabolic adaptations remain unclear. Here we show fragmented mitochondrial puncta in latent brain metastatic (Lat) cells enable fatty acid oxidation (FAO) to sustain cellular bioenergetics and maintain redox homeostasis. Depleting the enriched dynamin-related protein 1 (DRP1) and limiting mitochondrial plasticity in Lat cells results in increased lipid droplet accumulation, impaired FAO and attenuated metastasis. Likewise, pharmacological inhibition of DRP1 using a small-molecule brain-permeable inhibitor attenuated metastatic burden in preclinical models. In agreement with these findings, increased phospho-DRP1 expression was observed in metachronous brain metastasis compared with patient-matched primary tumors. Overall, our findings reveal the pivotal role of mitochondrial plasticity in supporting the survival of Lat cells and highlight the therapeutic potential of targeting cellular plasticity programs in combination with tumor-specific alterations to prevent metastatic recurrences.
Topics: Humans; Female; Breast Neoplasms; Dynamins; Mitochondria; Cell Line, Tumor; Brain Neoplasms
PubMed: 37248394
DOI: 10.1038/s43018-023-00563-6