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Circulation Research Jun 2023
Topics: Humans; Mitophagy; Cardiomyopathies; Heart; Dynamins; Mitochondrial Dynamics
PubMed: 37347834
DOI: 10.1161/CIRCRESAHA.123.323013 -
Neuron Sep 2022Dynamin mediates fission of vesicles from the plasma membrane during endocytosis. Typically, dynamin is recruited from the cytosol to endocytic sites, requiring seconds...
Dynamin mediates fission of vesicles from the plasma membrane during endocytosis. Typically, dynamin is recruited from the cytosol to endocytic sites, requiring seconds to tens of seconds. However, ultrafast endocytosis in neurons internalizes vesicles as quickly as 50 ms during synaptic vesicle recycling. Here, we demonstrate that Dynamin 1 is pre-recruited to endocytic sites for ultrafast endocytosis. Specifically, Dynamin 1xA, a splice variant of Dynamin 1, interacts with Syndapin 1 to form molecular condensates on the plasma membrane. Single-particle tracking of Dynamin 1xA molecules confirms the liquid-like property of condensates in vivo. When Dynamin 1xA is mutated to disrupt its interaction with Syndapin 1, the condensates do not form, and consequently, ultrafast endocytosis slows down by 100-fold. Mechanistically, Syndapin 1 acts as an adaptor by binding the plasma membrane and stores Dynamin 1xA at endocytic sites. This cache bypasses the recruitment step and accelerates endocytosis at synapses.
Topics: Dynamin I; Dynamins; Endocytosis; Nerve Tissue Proteins; Synaptic Vesicles
PubMed: 35809574
DOI: 10.1016/j.neuron.2022.06.010 -
Circulation Mar 2016Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance...
BACKGROUND
Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance during cardiac hypertrophy are not well understood.
METHODS AND RESULTS
Mice were subjected to transverse aortic constriction (TAC) and observed at multiple time points up to 30 days. Cardiac hypertrophy developed after 5 days, the ejection fraction was reduced after 14 days, and heart failure was observed 30 days after TAC. General autophagy was upregulated between 1 and 12 hours after TAC but was downregulated below physiological levels 5 days after TAC. Mitochondrial autophagy, evaluated by electron microscopy, mitochondrial content, and Keima with mitochondrial localization signal, was transiently activated at ≈3 to 7 days post-TAC, coinciding with mitochondrial translocation of Drp1. However, it was downregulated thereafter, followed by mitochondrial dysfunction. Haploinsufficiency of Drp1 abolished mitochondrial autophagy and exacerbated the development of both mitochondrial dysfunction and heart failure after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on day 7 after TAC, partially rescued mitochondrial autophagy and attenuated mitochondrial dysfunction and heart failure induced by overload. Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy.
CONCLUSIONS
Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to pressure overload. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and heart failure, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during pressure overload.
Topics: Amino Acid Sequence; Animals; Autophagy; Dynamins; Heart Failure; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitochondria; Molecular Sequence Data; Pressure
PubMed: 26915633
DOI: 10.1161/CIRCULATIONAHA.115.020502 -
Cells Aug 2022Endocytosis is a fundamental mechanism by which cells perform housekeeping functions. It occurs via a variety of mechanisms and involves many regulatory proteins. The... (Review)
Review
Endocytosis is a fundamental mechanism by which cells perform housekeeping functions. It occurs via a variety of mechanisms and involves many regulatory proteins. The GTPase dynamin acts as a "molecular scissor" to form endocytic vesicles and is a critical regulator among the proteins involved in endocytosis. Some GTPases (e.g., Cdc42, arf6, RhoA), membrane proteins (e.g., flotillins, tetraspanins), and secondary messengers (e.g., calcium) mediate dynamin-independent endocytosis. These pathways may be convergent, as multiple pathways exist in a single cell. However, what determines the specific path of endocytosis is complex and challenging to comprehend. This review summarizes the mechanisms of dynamin-independent endocytosis, the involvement of microRNAs, and factors that contribute to the cellular decision about the specific route of endocytosis.
Topics: Dynamins; Endocytosis; Transport Vesicles
PubMed: 36010634
DOI: 10.3390/cells11162557 -
Redox Biology Apr 2024Heart failure with preserved ejection fraction (HFpEF) is a devastating health issue although limited knowledge is available for its pathogenesis and therapeutics. Given...
AIMS
Heart failure with preserved ejection fraction (HFpEF) is a devastating health issue although limited knowledge is available for its pathogenesis and therapeutics. Given the perceived involvement of mitochondrial dysfunction in HFpEF, this study was designed to examine the role of mitochondrial dynamics in the etiology of HFpEF.
METHOD AND RESULTS
Adult mice were placed on a high fat diet plus l-NAME in drinking water ('two-hit' challenge to mimic obesity and hypertension) for 15 consecutive weeks. Mass spectrometry revealed pronounced changes in mitochondrial fission protein Drp1 and E3 ligase FBXL4 in 'two-hit' mouse hearts. Transfection of FBXL4 rescued against HFpEF-compromised diastolic function, cardiac geometry, and mitochondrial integrity without affecting systolic performance, in conjunction with altered mitochondrial dynamics and integrity (hyperactivation of Drp1 and unchecked fission). Mass spectrometry and co-IP analyses unveiled an interaction between FBXL4 and Drp1 to foster ubiquitination and degradation of Drp1. Truncated mutants of FBXL4 (Delta-Fbox) disengaged interaction between FBXL4 and Drp1. Metabolomic and proteomics findings identified deranged fatty acid and glucose metabolism in HFpEF patients and mice. A cellular model was established with concurrent exposure of high glucose and palmitic acid as a 'double-damage' insult to mimic diastolic anomalies in HFpEF. Transfection of FBXL4 mitigated 'double-damage'-induced cardiomyocyte diastolic dysfunction and mitochondrial injury, the effects were abolished and mimicked by Drp1 knock-in and knock-out, respectively. HFpEF downregulated sarco(endo)plasmic reticulum (SR) Ca uptake protein SERCA2a while upregulating phospholamban, RYR1, IP3R1, IP3R3 and Na-Ca exchanger with unaltered SR Ca load. FBXL4 ablated 'two-hit' or 'double-damage'-induced changes in SERCA2a, phospholamban and mitochondrial injury.
CONCLUSION
FBXL4 rescued against HFpEF-induced cardiac remodeling, diastolic dysfunction, and mitochondrial injury through reverting hyperactivation of Drp1-mediated mitochondrial fission, underscoring the therapeutic promises of FBXL4 in HFpEF.
Topics: Humans; Mice; Animals; Heart Failure; Mitochondrial Dynamics; Stroke Volume; Myocytes, Cardiac; Cardiomyopathies; Dynamins
PubMed: 38359748
DOI: 10.1016/j.redox.2024.103081 -
Nature Communications Jul 2023The large cytosolic GTPase, dynamin-related protein 1 (Drp1), mediates both physiological and pathological mitochondrial fission. Cell stress triggers Drp1 binding to...
The large cytosolic GTPase, dynamin-related protein 1 (Drp1), mediates both physiological and pathological mitochondrial fission. Cell stress triggers Drp1 binding to mitochondrial Fis1 and subsequently, mitochondrial fragmentation, ROS production, metabolic collapse, and cell death. Because Drp1 also mediates physiological fission by binding to mitochondrial Mff, therapeutics that inhibit pathological fission should spare physiological mitochondrial fission. P110, a peptide inhibitor of Drp1-Fis1 interaction, reduces pathology in numerous models of neurodegeneration, ischemia, and sepsis without blocking the physiological functions of Drp1. Since peptides have pharmacokinetic limitations, we set out to identify small molecules that mimic P110's benefit. We map the P110-binding site to a switch I-adjacent grove (SWAG) on Drp1. Screening for SWAG-binding small molecules identifies SC9, which mimics P110's benefits in cells and a mouse model of endotoxemia. We suggest that the SWAG-binding small molecules discovered in this study may reduce the burden of Drp1-mediated pathologies and potentially pathologies associated with other members of the GTPase family.
Topics: Animals; Mice; Allosteric Site; Disease Models, Animal; Dynamins; GTP Phosphohydrolases; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins
PubMed: 37468472
DOI: 10.1038/s41467-023-40043-0 -
Cell Communication and Signaling : CCS Apr 2015Dynamin is a GTPase protein that is essential for membrane fission during clathrin-mediated endocytosis in eukaryotic cells. Dynasore is a GTPase inhibitor that rapidly... (Review)
Review
Dynamin is a GTPase protein that is essential for membrane fission during clathrin-mediated endocytosis in eukaryotic cells. Dynasore is a GTPase inhibitor that rapidly and reversibly inhibits dynamin activity, which prevents endocytosis. However, comparison between cells treated with dynasore and RNA interference of genes encoding dynamin, reveals evidence that dynasore reduces labile cholesterol in the plasma membrane, and disrupts lipid raft organization, in a dynamin-independent manner. To explore the role of dynamin it is important to use multiple dynamin inhibitors, alongside the use of dynamin mutants and RNA interference targeting genes encoding dynamin. On the other hand, dynasore provides an interesting tool to explore the regulation of cholesterol in plasma membranes.
Topics: Animals; Cell Membrane; Cholesterol; Dynamins; Enzyme Inhibitors; Humans; Hydrazones
PubMed: 25889964
DOI: 10.1186/s12964-015-0102-1 -
Oxidative Medicine and Cellular... 2022Stroke is one of the leading causes of death and disability in the world. However, the pathophysiological process of stroke is still not fully clarified. Mitochondria... (Review)
Review
Stroke is one of the leading causes of death and disability in the world. However, the pathophysiological process of stroke is still not fully clarified. Mitochondria play an important role in promoting nerve survival and are an important drug target for the treatment of stroke. Mitochondrial dysfunction is one of the hallmarks of stroke. Mitochondria are in a state of continuous fission and fusion, which are termed as mitochondrial dynamics. Mitochondrial dynamics are very important for maintaining various functions of mitochondria. In this review, we will introduce the structure and functions of mitochondrial fission and fusion related proteins and discuss their role in the pathophysiologic process of stroke. A better understanding of mitochondrial dynamin in stroke will pave way for the development of new therapeutic options.
Topics: Drug Delivery Systems; Dynamins; Humans; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Stroke
PubMed: 35571256
DOI: 10.1155/2022/2504798 -
Redox Biology Dec 2022Hydrogen sulfide (HS), produced by cystathionine γ lyase (CSE), is an important endogenous gasotransmitter to maintain heart function. However, the molecular mechanism...
Hydrogen sulfide (HS), produced by cystathionine γ lyase (CSE), is an important endogenous gasotransmitter to maintain heart function. However, the molecular mechanism for how HS influences the mitochondrial morphology during heart failure remains poorly understood. Here, we found that CSE/HS pathway mediated cardiac function and mitochondrial morphology through regulating dynamin related protein 1 (Drp1) activity and translocation. Mechanistically, elevation of HS levels by CSE overexpression declined protein level, phosphorylation (Ser 616), oligomerization and GTPase activity of Drp1 by S-sulfhydration in mouse hearts. Interestingly, Drp1 S-sulfhydration directly competed with S-nitrosylation by nitric oxide at the specific cysteine 607. The non-S-sulfhydration of Drp1 mutation (C607A) attenuated the regulatory effect of HS on Drp1 activation, mitochondrial fission and heart function. Moreover, the non-canonical role of Drp1 mediated isoprenaline-induced mitochondrial dysfunction and cardiomyocyte death through interaction with voltage-dependent anion channel 1. These results uncover that a novel mechanism that HS S-sulfhydrated Drp1 at cysteine 607 to prevent heart failure through modulating its activity and mitochondrial translocation. Our findings also provide initial evidence demonstrating that Drp1 may be a critical regulator as well as an effective strategy for heart dysfunction.
Topics: Mice; Animals; Cystathionine gamma-Lyase; Cysteine; Hydrogen Sulfide; Dynamins; Heart Failure
PubMed: 36327794
DOI: 10.1016/j.redox.2022.102519 -
The EMBO Journal Nov 2016The large GTPase dynamin is the first protein shown to catalyze membrane fission. Dynamin and its related proteins are essential to many cell functions, from endocytosis... (Review)
Review
The large GTPase dynamin is the first protein shown to catalyze membrane fission. Dynamin and its related proteins are essential to many cell functions, from endocytosis to organelle division and fusion, and it plays a critical role in many physiological functions such as synaptic transmission and muscle contraction. Research of the past three decades has focused on understanding how dynamin works. In this review, we present the basis for an emerging consensus on how dynamin functions. Three properties of dynamin are strongly supported by experimental data: first, dynamin oligomerizes into a helical polymer; second, dynamin oligomer constricts in the presence of GTP; and third, dynamin catalyzes membrane fission upon GTP hydrolysis. We present the two current models for fission, essentially diverging in how GTP energy is spent. We further discuss how future research might solve the remaining open questions presently under discussion.
Topics: Animals; Cell Membrane; Dynamins; Guanosine Triphosphate; Humans
PubMed: 27670760
DOI: 10.15252/embj.201694613