Open AccessAmelioration of Ischemic Mitochondrial Injury and Bax‐Dependent Outer Membrane Permeabilization by Mdivi‐1
Author(s) -
Zhao YanXin,
Cui Mei,
Chen ShuFen,
Dong Qiang,
Liu XueYuan
Publication year - 2014
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12266
Subject(s) - mitochondrial fission , mitochondrion , apoptosis , mitochondrial fusion , microbiology and biotechnology , mitochondrial apoptosis induced channel , gene knockdown , mitochondrial permeability transition pore , programmed cell death , dnm1l , biology , inner mitochondrial membrane , pharmacology , chemistry , biochemistry , mitochondrial dna , gene
Summary Aims Disturbance of the balance between mitochondrial fission and fusion has been implicated in cerebral ischemia and several neurodegenerative diseases, whereas the underlying mechanisms remain poorly understood. In the present study, we attempted to investigate the role of dynamin‐related protein 1 (Drp1), a key mitochondrial fission protein, in the pathogenesis of cerebral ischemia. Methods Using Drp1 si RNA or Mdivi‐1, a small molecule inhibitor of Drp1, we examined the effect of Drp1 knockdown or inhibition on oxygen‐glucose deprivation ( OGD )‐induced mitochondrial dysfunction and death of SH ‐ SY ‐5Y cells. Cell death and viability were evaluated with LDH and MTT assays, respectively, and mitochondrial morphology, mitochondrial membrane potential ( Δψm ), and ATP production were assessed using epifluorescence microscopy, flow cytometry, and HPLC , respectively. Moreover, to examine the effect of Drp1 inhibition on ischemic brain injury, middle cerebral artery occlusion ( MCAO ) mice were injected (i.p.) with Mdivi1, and blood–brain barrier permeability, brain water content, and cell apoptosis were assessed. Results Knockdown or inhibition of Drp1 by Mdivi‐1 significantly attenuated OGD ‐induced cell death in SH ‐ SY ‐5Y cells, associated with reduced morphological change of mitochondria and attenuated Bax insertion,oligomerization. Moreover, treatment of the MCAO mice with Mdivi‐1 remarkably reduced the infarct volume and neurological deficits in a dose‐dependent manner, associated with marked reduction of mitochondrial fragmentation and BAX expression. Conclusions Down‐regulation or inhibition of Drp1 may reduce cerebral ischemic damage through maintaining normal mitochondrial morphology and function, and decreasing Bax insertion and oligomerization in mitochondria.