title: Mitochondrial dynamics following global cerebral ischemia.
abstract: 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 Opa1 oligomers. Opa1 has two known functions: maintenance of the cristae junction and mitochondrial fusion. These roles suggest that Opa1 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 Opa1. Moreover, we uncovered evidence of loss of Opa1 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 Opa1 alterations and dysfunctional mitochondrial dynamics following global brain ischemia.
authors: Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, United States; Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, United States; Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors: Rita
authors: R
authors: Kumar
authors: Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, United States; Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, United States; Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors: Melissa J
authors: MJ
authors: Bukowski
authors: Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, United States; Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors: Joseph M
authors: JM
authors: Wider
authors: Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, United States; Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, United States; Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors: Christian A
authors: CA
authors: Reynolds
authors: Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, United States; Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, United States; Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors: Lesley
authors: L
authors: Calo
authors: Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, United States; Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors: Bradley
authors: B
authors: Lepore
authors: Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, United States; Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors: Renee
authors: R
authors: Tousignant
authors: Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, United States; Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors: Michelle
authors: M
authors: Jones
authors: Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, United States; Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, United States; Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors: Karin
authors: K
authors: Przyklenk
authors: Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, United States; Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, United States. Electronic address: tsanders@med.wayne.edu.
authors: Thomas H
authors: TH
authors: Sanderson
mesh_terms: D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000098:blood supply / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D002478:Cells, Cultured; D020558:GTP Phosphohydrolases / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D063154:Mitochondrial Dynamics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*
chemical_list: D020558:GTP Phosphohydrolases; C498811:Opa1 protein, rat
keywords: Brain ischemia; Mitochondrial dynamics; Opa1; Reperfusion