Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8322450 | The International Journal of Biochemistry & Cell Biology | 2015 | 32 Pages |
Abstract
Mitochondrial dynamics play a critical role in mitochondrial function and signaling. Although mitochondria play a critical role in hypoxia/ischemia, the further mechanisms between mitochondrial dynamics and ischemia are still unclear. The current study aimed to determine the role of mitofusin 2, a key regulator of mitochondrial fusion, in a hypoxic model and to explore a novel strategy for cerebral ischemia via modulation of mitochondrial dynamics. To the best of our knowledge, this is the first study to investigate both mitochondrial function and molecular pathways to determine the role of mitofusin 2 in hypoxia-induced neuronal apoptosis. In vivo, C57BL/6 mice (male, 19-25 g) underwent a permanent middle cerebral artery occlusion for 12 or 24 h (n = 6 per group). In vitro, cobalt chloride was used to mimic hypoxia in immortalized hippocampal neurons. Down- or up-regulation of Mfn2 was induced to investigate the role of Mfn2 in hypoxia, especially in mitochondrial function and signaling pathways. The findings demonstrated that decreased mitofusin 2 occurred both in vivo and in vitro hypoxic models; second, the anti-apoptotic effect of Mfn2 may work via restoration of mitochondrial function; third, the modulation of the B Cell Leukemia 2/Bcl-2 Associated X protein and extracellular signal-regulated kinase 1/2 signaling pathways highlight the role of Mfn2 in signaling pathways beyond fusion. In summary, depletion of mitofusin 2 would lead to apoptosis both in normal or hypoxic conditions; however, mitofusin 2 overexpression could attenuate hypoxia-induced apoptosis, which represents a potential novel strategy for neuroprotection against ischemic brain damage.
Keywords
ECAMPTPCCABcl-2GAPDHMCAODrp1ICACoCl2DMEMHT22Mitochondrial outer membrane permeabilityCCK-8MMPTMRMPBSBcl-2/BaxERK1/2opa1MAPKDulbecco's modified Eagle's mediumROSAdenosine TriphosphateATPCritical thresholdAIFmitochondrial permeability transition poremiddle cerebral artery occlusionBaxanalysis of varianceANOVAterminal deoxynucleotidyl transferase dUTP nick-end labelingTUNELApoptosisexternal carotid arteryinternal carotid arterycommon carotid arterycell counting kit-8apoptosis-inducing factorMitochondrial functionHypoxia-inducible factorMOMPPhosphate-buffered salinemitofusin 2Hippocampal neuronspolymerase chain reactionPCRMitochondrial membrane potentialBcl-2 Associated X proteinoptic atrophy protein 1dynamin-related protein 1Cobalt chlorideextracellular signal-regulated kinase 1/2mitogen-activated protein kinasesglyceraldehyde-3-phosphate dehydrogenaseReactive oxygen species
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Authors
Cheng Peng, Wei Rao, Lei Zhang, Kai Wang, Hao Hui, Li Wang, Ning Su, Peng Luo, Ye-lu Hao, Yue Tu, Sai Zhang, Zhou Fei,