Drp1タンパク質のシステイン修飾を介したミトコンドリア過剰分裂を伴う心筋老化
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Methylmercury (MeHg) is an electrophilic environmental neurotoxicant that is biologically concentrated into seafood. High-dose MeHg exposure leads covalent modification of protein thiol groups to form S-mercuration (MeHg-S-protein). This pathological protein modification, in part, explains the neurotoxicity of MeHg. Epidemiological studies have also suggested that MeHg increases cardiac risk at a lower concentration than that associated with neurotoxicity. However, the underlying mechanism is unclear. We previously identified that aberrant mitochondrial fission induced by hypoxic stress cause cardiac vulnerability. Here we show that exposure to a low dose of MeHg increased cardiac risk induced by pressure overload in mice. MeHg exposure caused mitochondrial hyperfission in myocardium through the activation of mitochondrial fission factor Drp1. MeHg treatment promoted Drp1 activation by increasing the interaction between Drp1 and its guanine nucleotide exchange factor filamin A. Modification of cysteine residues in proteins with polysulfides play an indispensable role in redox signaling and mitochondrial homeostasis in mammalian cells. Drp1 activity was negatively regulated by polysulfidation at Cys624, a redox-sensitive residue. MeHg exposure induced the depolysulfidation of Cys624 in Drp1, which led to filamin A-dependent activation of Drp1 and mitochondrial hyperfission. Other environmental pollutant, cigarette sidestream smoke that is a significant contributor to increased cardiovascular mortality also led cardiomyocyte dysfunction through Drp1 depolysulfidation. Treatment with NaHS, which acts as a donor for reactive polysulfides, reversed MeHg-evoked Drp1 depolysulfidation and vulnerability to mechanical load in rodent and human cardiomyocytes and mouse hearts. These results suggest that depolysulfidation of Drp1 at Cys624 by environmental stress such as MeHg increases cardiac fragility to mechanical load through filamin-dependent mitochondrial hyperfission.Keywords:
Neurotoxicity
Methylmercury
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Methylmercury
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Summary Aims Prolonged seizure activity may result in mitochondrial dysfunction and lead to cell death in the hippocampus. Mitochondrial fission may occur in an early stage of neuronal cell death. This study examined the role of the mitochondrial fission protein dynamin‐related protein 1 (Drp1) in the hippocampus following status epilepticus. Methods Kainic acid ( KA ) was microinjected unilaterally into the hippocampal CA 3 area in Sprague Dawley rats to induce prolonged seizure activity. Biochemical analysis, electron microscopy, and immunofluorescence staining were performed to evaluate the subsequent molecular and cellular events. The effects of pretreatment with a mitochondrial fission protein inhibitor, Mdivi‐1 (2 nmol), were also evaluated. Results Phosphorylation of Drp1 at serine 616 (p‐Drp1(Ser616)) was elevated from 1 to 24 h after the elicited seizure activity. Pretreatment with Mdivi‐1 decreased the Drp1 phosphorylation at Ser616 and limited the mitochondrial fission. Mdivi‐1 rescued the Complex I dysfunction, decreased the levels of oxidized proteins, decreased the activation of cytochrome c /caspase‐3 signaling, and blunted cell death in CA 3 neurons. Conclusion Our findings suggest that activation of p‐Drp1(Ser616) is related to seizure‐induced neuronal damage. Modulation of p‐Drp1(Ser616) expression is accompanied by decreases in mitochondrial fission, mitochondrial dysfunction, and oxidation, providing a neuroprotective effect against seizure‐induced hippocampal neuronal damage.
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Dynamin-related protein 1 (Drp1) is a major protein for regulating mitochondrial fission. Its activity is associated with the post-translational modification, mainly including phosphorylation, ubiquitination, sumoylation, and S-nitrosylation. During the cerebral ischemia, Drp1 is activated and translocates from the cytoplasm to the mitochondrial outer membrane, mediates mitochondrial fission and eliminates damaged mitochondria. Drp1 plays the important roles in the pathological processes of ischemic neuronal apoptosis, necrotic apoptosis, and mitophagy. Excessive mitochondria fission or accumulation of damaged mitochondria will aggravate neuronal injury.
Key words:
Dynamins; Mitochondria; Reactive Oxygen Species; Brain Ischemia
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Mitochondrial apoptosis-induced channel
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The long-term usage of doxorubicin (DOX) is largely limited due to the development of severe cardiomyopathy. Many studies indicate that DOX-induced cardiac injury is related to reactive oxygen species generation and ultimate activation of apoptosis. The role of novel mitochondrial fission protein 1 (Mtfp1) in DOX-induced cardiotoxicity remains elusive. Here, we report the pro-mitochondrial fission and pro-apoptotic roles of Mtfp1 in DOX-induced cardiotoxicity. DOX up-regulates the Mtfp1 expression in HL-1 cardiac myocytes. Knockdown of Mtfp1 prevents cardiac myocyte from undergoing mitochondrial fission, and subsequently reduces the DOX-induced apoptosis by preventing dynamin 1-like (Dnm1l) accumulation in mitochondria. In contrast, when Mtfp1 is overexpressed, a suboptimal dose of DOX can induce a significant percentage of cells to undergo mitochondrial fission and apoptosis. These data suggest that knocking down of Mtfp1 can minimize the cardiomyocytes loss in DOX-induced cardiotoxicity. Thus, the regulation of Mtfp1 expression could be a novel therapeutic approach in chemotherapy-induced cardiotoxicity.
Cardiotoxicity
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Mitochondrial apoptosis-induced channel
DNAJA3
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Brain is the main target organ poisoned by methylmercury,the mechanism of the neurotoxicity is still not quite clear.It was suggested that oxidative damage might play a key role in methylmercury induced neurotoxicity.Antioxidants are a kind of the substances with low toxicity and high bioactivity.In this paper,the mechanisms of neurotoxicity casued by methylmercury and the antagonistic effect of antioxidants were reviewed.
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Methylmercury
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Hydrogen sulfide (H2S) has been demonstrated to have various effects on mitochondrial function. The aim of the present study was to investigate the effects of H2S on mitochondrial fission and the potential underlying mechanisms of these effects. Transmission electron microscopy analysis demonstrated that sodium hydrosulfide (NaHS, a donor of H2S) inhibited mitochondrial fission in a dose‑ and time‑dependent manner. Treating neuro‑2a (N2a) mouse neuroblastoma cells with 400 µM NaHS for 16 h significantly increased the % of elongated mitochondria and reduced the number of mitochondria per cell compared with untreated cells. In addition, the viability and ATP generation of N2a cells that were treated with various concentrations of NaHS was examined. The results demonstrated that treatment with 400 and 600 µM NaHS increased cell viability and ATP generation compared with untreated cells. To further understand the effects of H2S on mitochondrial morphology, the protein and mRNA expression levels of dynamin 1 like (Dnm1l, also known as Drp1) were examined, and the results demonstrated that NaHS dose‑dependently reduced Drp1 mRNA and protein levels, consistent with the mitochondrial morphology changes. To determine whether H2S affects mitochondrial morphology through Drp1 expression, Drp1 was overexpressed in N2a cells using a lentivirus encoding the Drp1 cDNA. It was observed that Drp1 overexpression reversed the effects of NaHS. Furthermore, NaHS promoted the phosphorylation of extracellular signal‑regulated kinase (ERK) 1/2, and the effects of NaHS on Drp1 expression were abolished by an ERK1/2 inhibitor (PD98059). The results of the present study indicate that the H2S‑induced decrease in Drp1 mRNA and protein levels and mitochondrial fission may involve the ERK1/2 signaling pathway. The present study suggests that H2S may be used in the future as a potential therapeutic for diseases that may be mediated by abnormal mitochondria fragmentation, such as Alzheimer's disease.
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Sodium hydrosulfide
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MFN2
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Abstract Mitochondria are in a constant balance of fusing and dividing in response to cellular cues. Fusion creates healthy mitochondria, whereas fission results in removal of non-functional organelles. Changes in mitochondrial dynamics typify several human diseases. However, the contribution of mitochondrial dynamics to preeclampsia, a hypertensive disorder of pregnancy characterized by placental cell autophagy and death, remains unknown. Herein, we show that the mitochondrial dynamic balance in preeclamptic placentae is tilted toward fission (increased DRP1 expression/activation and decreased OPA1 expression). Increased phosphorylation of DRP1 (p-DRP1) in mitochondrial isolates from preeclamptic placentae and transmission electron microscopy corroborated augmented mitochondrial fragmentation in cytotrophoblast cells of PE placentae. Increased fission was accompanied by build-up of ceramides (CERs) in mitochondria from preeclamptic placentae relative to controls. Treatment of human choriocarcinoma JEG3 cells and primary isolated cytrophoblast cells with CER 16:0 enhanced mitochondrial fission. Loss- and gain-of-function experiments showed that Bcl-2 member BOK, whose expression is increased by CER, positively regulated p-DRP1/DRP1 and MFN2 expression, and localized mitochondrial fission events to the ER/MAM compartments. We also identified that the BH3 and transmembrane domains of BOK were vital for BOK regulation of fission. Moreover, we found that full-length PTEN-induced putative kinase 1 (PINK1) and Parkin, were elevated in mitochondria from PE placentae, implicating mitophagy as the process that degrades excess mitochondria fragments produced from CER/BOK-induced fission in preeclampsia. In summary, our study uncovered a novel CER/BOK-induced regulation of mitochondrial fission and its functional consequence for heightened trophoblast cell autophagy in preeclampsia.
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DNM1L
FIS1
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