Effect Of Mdivi-1 Research Articles

Therapeutic Effect of Mitochondrial Division Inhibitor-1 (Mdivi-1) on Hyperglycemia-Exacerbated Early and Delayed Brain Injuries after Experimental Subarachnoid Hemorrhage.

Background: Neurological deficits following subarachnoid hemorrhage (SAH) are caused by early or delayed brain injuries. Our previous studies have demonstrated that hyperglycemia induces profound neuronal apoptosis of the cerebral cortex. Morphologically, we found that hyperglycemia exacerbated late vasospasm following SAH. Thus, our previous studies strongly suggest that post-SAH hyperglycemia is not only a response to primary insult, but also an aggravating factor for brain injuries. In addition, mitochondrial fusion and fission are vital to maintaining cellular functions. Current evidence also shows that the suppression of mitochondrial fission alleviates brain injuries after experimental SAH. Hence, this study aimed to determine the effects of mitochondrial dynamic modulation in hyperglycemia-related worse SAH neurological prognosis. Materials and methods: In vitro, we employed an enzyme-linked immunosorbent assay (ELISA) to detect the effect of mitochondrial division inhibitor-1 (Mdivi-1) on lipopolysaccharide (LPS)-induced BV-2 cells releasing inflammatory factors. In vivo, we produced hyperglycemic rats via intraperitoneal streptozotocin (STZ) injections. Hyperglycemia was confirmed using blood-glucose measurements (>300 mg/dL) 7 days after the STZ injection. The rodent model of SAH, in which fresh blood was instilled into the craniocervical junction, was used 7 days after STZ administration. We investigated the mechanism and effect of Mdivi-1, a selective inhibitor of dynamin-related protein (Drp1) to downregulate mitochondrial fission, on SAH-induced apoptosis in a hyperglycemic state, and evaluated the results in a dose–response manner. The rats were divided into the following five groups: (1) control, (2) SAH only, (3) Diabetes mellitus (DM) + SAH, (4) Mdivi-1 (0.24 mg/kg) + DM + SAH, and (5) Mdivi-1 (1.2 mg/kg) + DM + SAH. Results: In vitro, ELISA revealed that Mdivi-1 inhibited microglia from releasing inflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. In vivo, neurological outcomes in the high-dose (1.2 mg/kg) Mdivi-1 treatment group were significantly reduced compared with the SAH and DM + SAH groups. Furthermore, immunofluorescence staining and ELISA revealed that a high dose of Mdivi-1 had attenuated inflammation and neuron cell apoptosis by inhibiting Hyperglycemia-aggravated activation, as well as microglia and astrocyte proliferation, following SAH. Conclusion: Mdivi-1, a Drp-1 inhibitor, attenuates cerebral vasospasm, poor neurological outcomes, inflammation, and neuron cell apoptosis following SAH + hyperglycemia.

Mdivi-1 alleviates cardiac fibrosis post myocardial infarction at infarcted border zone, possibly via inhibition of Drp1-Activated mitochondrial fission and oxidative stress

Mitochondrial division inhibitor 1(Mdivi-1) has been shown to play a beneficial role in a variety of diseases, mainly by inhibiting Drp1-mediated mitochondrial fission. The effects of Mdivi-1 on cardiac fibrosis at infarcted border zone area and its possible mechanism remain unclear. This study aimed to investigate the effects of Mdivi-1 on reactive cardiac fibrosis and cardiac function post myocardial infarction and its potential mechanisms. Mice were randomly divided into six groups (n = 9 for each group): Sham; Mdivi-1; MI 7d; MI 14d; MI 28d; MI 28d + Mdivi-1. The MI model was induced by ligation of LAD coronary artery. Mdivi-1 (1 mg/kg) was administered to mice every other day at a time from the second day until the sacrifice of the mice (total 14 injection of Mdivi-1). In vitro experiments, the effect of Mdivi-1 on TGF-β1-induced fibrosis-related pathophysiological changes of fibroblasts was examined in NIH3T3 cells. We found that Mdivi-1 significantly attenuated fibroblast activation, collagen production and fibrosis at infarcted border zone after MI, improved impaired heart function. Mechanistically, we observed that Mdivi-1 reduced the protein expression of P-Drp1-S616 and abnormal mitochondrial fission of cardiac fibroblasts in the infarcted border zone area. In addition, we found that the effects of Mdivi-1 partially relied on increasing the expression of Hmox1 and inhibiting oxidative stress. In conclusion, Mdivi-1 could attenuate cardiac fibrosis at infarcted border zone and improve impaired heart function partially through attenuation of Drp1-mediated mitochondrial fission. Moreover, inhibition of oxidative stress, which is possible due to the up-regulation of Hmox1, may be another potential mechanism of action of Mdivi-1.

O36. Mitochondrial dynamics as a potential target for cancer therapy

Introduction Mitochondria are important organelles that control metabolism and cell death. Cellular mitochondrial status, including mitochondrial dynamics, may determine tumour radioresponsiveness. The aim of this study was to characterise mitochondrial status in cancer cells, modulate mitochondrial dynamics and assess changes in cell survival and response to radiation therapy. Materials and methods Mitochondrial dynamics was assessed using the MitoTracker red staining technique and microscopic evaluation. Respiratory status and mitochondrial membrane potential were analysed and correlated with radiation survival in several cancer cell lines. Modulation of mitochondrial dynamics was achieved using the fission inhibitor Mdivi-1. Cell survival assays were employed to determine the effect of Mdivi-1 on cellular radiation response. Mechanistic aspects were explored by assessment of apoptosis, cell cycle dynamics and cytogenetic effects of Mdivi-1. Results Inhibition of fission by Mdivi-1 induced a measureable increase in fusion and caused significant cytotoxicity. Mdivi-1 was shown to significantly increase cellular radiosensitivity. Differences in cell survival were associated with cell cycle arrest and increased apoptosis. Mdivi-1 treatment induced micronuclei and enhanced radiation-induced cytogenetic damage. No influence on radiation repair was detected. Conclusion Results of this study suggest that regulation of mitochondrial dynamics is an important aspect of cellular function that may influence the response of cancer cells to therapy. While no firm correlation could be established between mitochondrial status and radiosensitivity, a novel scoring system was developed to assess mitochondrial fragmentation. Notably, modulation of mitochondrial dynamics was found to facilitate both cytotoxicity and enhanced cellular response to radiotherapy. Therefore, modulation of mitochondrial dynamics may represent a novel approach to targeted cancer therapy.

Abstract 5085: Inducing multipolarity of acentrosomal mitotic spindles as a novel tumor-specific targeting strategy revealed by the antimitotic effect of mdivi-1

Abstract Traditional antimitotic drugs for cancer chemotherapy often have undesired toxicity to healthy tissue, limiting clinical application. Developing tumor-specific antimitotic strategies is necessary to improve the efficacy of drugs in the selective eradication of tumor cells. In this study, we discovered mdivi-1 (mitochondrial division inhibitor-1), which was originally reported as an inhibitor of mitochondrial fission protein dynamin-related protein 1 (Drp1), specifically disrupts M phase cell cycle progression only in human tumor cells and not in non-transformed fibroblasts and epithelial cells. The antimitotic effect of mdivi-1 is Drp1-independent, as M phase abnormality induced by mdivi-1 was observed in both Drp1 wild-type and Drp1 knockout MEF cells. We also identified that the tumor transformation process required for the antimitotic effect of mdivi-1 is downstream of SV40 large T and small t antigens - but not hTERT-mediated immortalization. Mdivi-1 induces multipolar mitotic spindles in tumor cells regardless of centrosome number. Acentrosomal spindle poles, which do not contain bona-fide centrosome components γ-tubulin and centrin-2, were found to contribute to the spindle multipolarity. The formation of such aberrant mitotic spindles leads to gross genome instability and apoptotic cell death through Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP). Gene expression profiling comparing non-transformed and transformed cells revealed that the genes involved in assembly of acentrosomal spindles are highly up-regulated in tumor cells, thus providing the mechanism underlying the preferential formation of acentrosomal multipolar spindles in tumor cells compared to normal cells after mdivi-1 treatment. Taken together, our studies imply that mdivi-1 represents a novel class of quinazolinone compounds that function as acentrosomal spindle inducers (ASI). We suggest that promoting the assembly of multipolar mitotic spindles composed of acentrosomal poles could serve as a novel strategy in achieving a tumor-specific antimitotic effect. (Work was supported by P30CA047904, GM087798, UPCI and PA Dept of Health CURE program) Note: This abstract was not presented at the meeting. Citation Format: Jingnan Wang, Wei Qian, Masahiro Shuda, Jianfeng Li, Lucas Santana-Santos, Robert W. Sobol, Bennett Van Houten. Inducing multipolarity of acentrosomal mitotic spindles as a novel tumor-specific targeting strategy revealed by the antimitotic effect of mdivi-1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5085. doi:10.1158/1538-7445.AM2014-5085

Dynamin-related protein Drp1 and mitochondria are important for Shigella flexneri infection

Shigella infection in epithelial cells induces cell death which is accompanied by mitochondrial dysfunction. In this study the role of the mitochondrial fission protein, Drp1 during Shigella infection in HeLa cells was examined. Significant lactate dehydrogenase (LDH) release was detected in the culture supernatant when HeLa cells were infected with Shigella at a high multiplicity of infection. Drp1 inhibition with Mdivi-1 and siRNA knockdown significantly reduced LDH release. HeLa cell death was also accompanied by mitochondrial fragmentation. Tubular mitochondrial networks were partially restored when Drp1 was depleted with either siRNA or inhibited with Mdivi-1. Surprisingly either Mdivi-1 treatment or Drp1 siRNA-depletion of HeLa cells also reduced Shigella plaque formation. The effect of Mdivi-1 on Shigella infection was assessed using the murine Sereny model, however it had no impact on ocular inflammation. Overall our results suggest that Drp1 and the mitochondria play important roles during Shigella infection.