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.

Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons

“…The consequences of transient cerebral ischemia are often severe and have selectively harmful effects on the vulnerable regions involving the pyramidal neurons of the CA1 hippocampus [17]. Therefore, it is necessary to determine the underlying mechanism of cerebral ischemia/reperfusion injury and to develop effective strategies to circumvent this pathological condition.…”

Mitochondrial Quality Control: Role in Cardiac Models of Lethal Ischemia-Reperfusion Injury

“…In addition, calcineurin activation results in the dephosphorylation of DRP1, thereby favoring fission [26,28,99], while OMA1 activation results in the proteolytic cleavage of OPA1 and resultant disruption of cristae architecture [151,153,157,172]. Finally, collapse of mitochondrial membrane potential and compromised mitochondrial integrity have been identified as drivers for pathological fission [28,173]. Thus, and perhaps not surprisingly, metabolic perturbations and changes in mitochondrial phenotype are integrated (rather than discrete) consequences of myocardial ischemia-reperfusion.…”

“…However, as in heart, the contribution of mitochondrial quality control to the pathogenesis of IR injury in brain remains incompletely understood and, in some cases, controversial. There is a clear consensus that IR is associated with mitochondrial fragmentation in the initial hours following relief of ischemia [85,173,[319][320][321][322][323], an observation that has been made following transient focal ischemia mimicking stroke [321] and following global cerebral ischemia mimicking cardiac arrest-resuscitation [85]. Increased fission has also been observed in neuronal cell culture models (including SH-SY-5Y cells, primary neurons and HT22 cells) subjected to oxygen-glucose deprivation (OGD) [173,322].…”

“…There is a clear consensus that IR is associated with mitochondrial fragmentation in the initial hours following relief of ischemia [85,173,[319][320][321][322][323], an observation that has been made following transient focal ischemia mimicking stroke [321] and following global cerebral ischemia mimicking cardiac arrest-resuscitation [85]. Increased fission has also been observed in neuronal cell culture models (including SH-SY-5Y cells, primary neurons and HT22 cells) subjected to oxygen-glucose deprivation (OGD) [173,322]. Moreover, intriguing data obtained from isolated neuronal models suggests that the temporal profile of mitochondrial fission may be complex and biphasic, with an initial, profound but transient episode of mitochondrial fragmentation during the early minutes post-reperfusion followed by a second and sustained period of fission after 2 h of reoxygenation [173].…”

Overexpression of apoptosis inducing factor aggravates hypoxic-ischemic brain injury in neonatal mice

“…Mitochondrial morphology is dynamically controlled by a balance between organelle fission and fusion 21 , and this dynamic equilibrium can be disrupted by AIF deficiency 22 . Studies show that mitochondrial dynamics can be disrupted by HI injury in the immature brain and by ischemia/reperfusion in the adult brain 18,[23][24][25][26][27] . Thus, mitochondrial dynamics might be related to the pathophysiological processes of HI-induced brain injury.…”