Mitochondrial dynamics following global cerebral ischemia

Rita Kumar, Melissa J. Bukowski, Joseph M. Wider, Christian A. Reynolds, Lesley Calo, Bradley Lepore, Renee Tousignant, Michelle Jones, Karin Przyklenk, Thomas H. Sanderson

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

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.

Original languageEnglish
Pages (from-to)68-75
Number of pages8
JournalMolecular and Cellular Neuroscience
Volume76
DOIs
StatePublished - Oct 1 2016

Keywords

  • Brain ischemia
  • Mitochondrial dynamics
  • Opa1
  • Reperfusion

Fingerprint

Dive into the research topics of 'Mitochondrial dynamics following global cerebral ischemia'. Together they form a unique fingerprint.

Cite this