title: Dynamin-related protein 1 inhibitors protect against ischemic toxicity through attenuating mitochondrial Ca2+ uptake from endoplasmic reticulum store in PC12 cells.
abstract: Intracellular calcium homeostasis disorder and mitochondrial dysfunction are involved in many acute and chronic brain diseases, including ischemic brain injury. An imbalance in mitochondrial fission and fusion is one of the most important structural abnormalities found in a large number of mitochondrial dysfunction related diseases. Here, we investigated the effects of mitochondrial division inhibitor A (mdivi A) and mdivi B, two small molecule inhibitors of mitochondrial fission protein dunamin-related protein 1 (Drp-1), in neuronal injury induced by oxygen-glucose deprivation (OGD) in PC12 cells. We found that mdivi A and mdivi B inhibited OGD-induced neuronal injury through attenuating apoptotic cell death. These two inhibitors also preserved mitochondrial function, as evidenced by reduced reactive oxygen species (ROS) generation and cytochrome c release, as well as prevented loss of mitochondrial membrane potential (MMP). Moreover, mdivi A and mdivi B significantly suppressed mitochondrial Ca(2+) uptake, but had no effect on cytoplasmic Ca(2+) after OGD injury. The results of calcium imaging and immunofluorescence staining showed that Drp-1 inhibitors attenuated endoplasmic reticulum (ER) Ca(2+) release and prevented ER morphological changes induced by OGD. These results demonstrate that Drp-1 inhibitors protect against ischemic neuronal injury through inhibiting mitochondrial Ca(2+) uptake from the ER store and attenuating mitochondrial dysfunction.
authors.affiliation: Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710003, Shaanxi, China. xijiaodatianye@163.com.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710003, Shaanxi, China. xijiaodalibin@163.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710003, Shaanxi, China. xijiaodashiwz@163.com.
authors.forename: Wen-Zhen
authors.initials: WZ
authors.lastname: Shi
authors.affiliation: Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710003, Shaanxi, China. xijiaodachangmz@163.com.
authors.forename: Ming-Ze
authors.initials: MZ
authors.lastname: Chang
authors.affiliation: Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710003, Shaanxi, China. xijiaodazhanggj@163.com.
authors.forename: Ge-Juan
authors.initials: GJ
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710003, Shaanxi, China. xijiaodadizl@163.com.
authors.forename: Zheng-Li
authors.initials: ZL
authors.lastname: Di
authors.affiliation: Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University School of Medicine, Xi'an 710061, Shaanxi, China. liuyong1961xa@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D045304:Cytochromes c; C519851:Dnm1l protein, rat; D034281:Dynamins; D002118:Calcium