title: Downregualtion of dynamin-related protein 1 attenuates glutamate-induced excitotoxicity via regulating mitochondrial function in a calcium dependent manner in HT22 cells.
abstract: Glutamate-mediated excitotoxicity is involved in many acute and chronic brain diseases. Dynamin related protein 1 (Drp-1), one of the GTPase family of proteins that regulate mitochondrial fission and fusion balance, is associated with apoptotic cell death in cancer and neurodegenerative diseases. Here we investigated the effect of downregulating Drp-1 on glutamate excitotoxicity-induced neuronal injury in HT22 cells. We found that downregulation of Drp-1 with specific small interfering RNA (siRNA) increased cell viability and inhibited lactate dehydrogenase (LDH) release after glutamate treatment. Downregulation of Drp-1 also inhibited an increase in the Bax/Bcl-2 ratio and cleavage of caspase-9 and caspase-3. Drp-1 siRNA transfection preserved the mitochondrial membrane potential (MMP), reduced cytochrome c release, enhanced ATP production, and partly prevented mitochondrial swelling. In addition, Drp-1 knockdown attenuated glutamate-induced increases of cytoplasmic and mitochondrial Ca(2+), and preserved the mitochondrial Ca(2+) buffering capacity after excitotoxicity. Taken together, these results suggest that downregulation of Drp-1 protects HT22 cells against glutamate-induced excitatory damage, and this neuroprotection may be dependent at least in part on the preservation of mitochondrial function through regulating intracellular calcium homeostasis.
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central-South University, Changsha, Hunan 410008, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central-South University, Changsha, Hunan 410008, China.
authors.forename: Xian-rui
authors.initials: XR
authors.lastname: Yuan
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central-South University, Changsha, Hunan 410008, China.
authors.forename: Hao-yu
authors.initials: HY
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central-South University, Changsha, Hunan 410008, China.
authors.forename: Zi-jin
authors.initials: ZJ
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central-South University, Changsha, Hunan 410008, China.
authors.forename: Yi-wei
authors.initials: YW
authors.lastname: Liao
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central-South University, Changsha, Hunan 410008, China.
authors.forename: Xiang-yu
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central-South University, Changsha, Hunan 410008, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central-South University, Changsha, Hunan 410008, China.
authors.forename: Shu-shan
authors.initials: SS
authors.lastname: Sang
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central-South University, Changsha, Hunan 410008, China. Electronic address: xiangyaliuqing@163.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D018698:Glutamic Acid; C486391:Dnm1l protein, mouse; D034281:Dynamins; D002118:Calcium
keywords: Apoptosis; Calcium; Drp-1; Excitotoxicity; Mitochondria