Mitochondrial dynamics following global cerebral ischemia

作者：Kumar Rita; Bukowski Melissa J; Wider Joseph M; Reynolds Christian A; Cabo Lesley; Lepore Bradley; Tousignant Renee; Jones Michelle; Przyklenk Karin; Sanderson Thomas H^*

来源：Molecular and Cellular Neuroscience, 2016, 76: 68-75.

DOI：10.1016/j.mcn.2016.08.010

• Brain ischemia
• Reperfusion
• Mitochondrial dynamics
• Opa1

Global brain ischemia/reperfusion induces neuronal damage in vulnerable brain regions, leading to mitochondrial dysfunction and subsequent neuronal death. Induction of neuronal death is mediated by release of cytochrome c (cyt c) from the mitochondria though a well-characterized increase in outer mitochondrial membrane permeability. However, for cyt c to be released it is first necessary for cyt c to be liberated from the cristae junctions which are gated by Opal oligomers. Opal has two known functions: maintenance of the cristae junction and mitochondrial fusion. These roles suggest that Opal could play a central role in both controlling cyt c release and mitochondrial fusion/fission processes during ischemia/reperfusion. To investigate this concept, we first utilized in vitro real-time imaging to visualize dynamic changes in mitochondria. Oxygen-glucose deprivation (OGD) of neurons grown in culture induced a dual-phase mitochondrial fragmentation profile: (i) fragmentation during OGD with no apoptosis activation, followed by fusion of mitochondrial networks after reoxygenation and a (ii) subsequent extensive fragmentation and apoptosis activation that preceded cell death. We next evaluated changes in mitochondrial dynamic state during reperfusion in a rat model of global brain ischemia. Evaluation of mitochondrial morphology with confocal and electron microscopy revealed a similar induction of fragmentation following global brain ischemia. Mitochondrial fragmentation aligned temporally with specific apoptotic events, including cyt c release, caspase 3/7 activation, and interestingly, release of the fusion protein Opal. Moreover, we uncovered evidence of loss of Opal complexes during the progression of reperfusion, and electron microscopy micrographs revealed a loss of cristae architecture following global brain ischemia. These data provide novel evidence implicating a temporal connection between Opal alterations and dysfunctional mitochondrial dynamics following global brain ischemia.

• 出版日期2016-10