Mitochondrial dynamics: cell-type and hippocampal region specific changes following global cerebral ischemia

Abstract

Mitochondria are organelles that undergo continuous cycles of fission and fusion. This dynamic nature of mitochondria is important for cell physiology. Transgenic mouse models that express mitochondria targeted fluorescence protein, in either neurons or astrocytes, were used to examine the role of alterations in mitochondrial morphology in mechanisms of ischemic brain injury. The animals were subjected to global cerebral ischemia and allowed to recover before their brains were perfusion fixed and processed for histology and confocal microscopy. After capturing z-stack images from different hippocampal sub-regions, mitochondrial organelles were 3D reconstructed using volocity software and then their morphological parameters were calculated. The data shows cell-type specific alterations in mitochondrial dynamics following ischemia. Fission is activated in all hippocampal areas at 2 h recovery with mitochondria in CA1 becoming progressively more fragmented during the 24 h recovery period. Mitochondria in CA3 and dentate gyrus neurons started to re-fuse after 24 h of recirculation; this was even more pronounced 3 days after ischemia. Astrocytic mitochondria underwent transient fission 2 h after ischemic insult and regained their normal shape at 24 h recovery. Surprisingly, no positive correlation was found between increased nitrotyrosine levels and mitochondrial fission, particularly in ischemia resistant CA3 and dentate gyrus neurons. Our data suggest that ischemia resistant neurons are able to shift their mitochondrial dynamics toward fusion after extensive fragmentation. The re-fusion ability of fragmented mitochondria is most likely a vital feature for cell survival.

Sex-dependent mitophagy and neuronal death following rat neonatal hypoxia–ischemia

“…Under stress and/or pathological conditions, mitochondria can undergo rapid fission, which is often referred to as fragmentation (Owens et al, 2015). There were no significant differences in total number of TOM20 particles (Fig.…”

“…These findings support the hypothesis that a mitochondrial mechanism may underlie the sex differences in long-term neurobehavioral outcome observed following HI. Mitochondrial fission (or fragmentation) (Pradeep et al, 2014; Zhang et al, 2015; Owens et al, 2015a) and autophagy (Weis et al, 2014; Li et al, 2015; Yu et al, 2015) are known to occur following cerebral ischemia–reperfusion injury. It is hypothesized that mitochondrial fragmentation segregates oxidatively modified mitochondrial proteins for elimination via mitochondrial-specific autophagy (mitophagy) (Twig et al, 2008; Soubannier et al, 2012; Norton et al, 2014).…”

Mitochondrial dynamics following global cerebral ischemia

“…Moreover, the pathophysiologic stress of ischemia-reperfusion will, in theory, ‘prime’ neurons for an up-regulation in fission [23–25]. There is morphologic evidence supporting mitochondrial fragmentation induction by ischemia-reperfusion, which is further strengthened with molecular data identifying interactions and interrelationships among key proteins involved in apoptosis, fission and fusion [13,5,6,4]. There has been considerable research focused on the fission protein, Drp1, as the connection between mitochondrial fragmentation and cell death.…”

“…Proteolytic processing and altered expression of Opa1 isoforms have been shown to play key roles in mitochondrial fusion, with disruptions in Opa1 isoforms promoting a mitochondrial fission phenotype [4,12]. Evidence supporting a post-ischemic increase in mitochondrial fragmentation was provided by mitochondrial-YFP reporter mice exposed to brain ischemia [13]. Indeed, mitochondrial fragmentation was observed following ischemia in the regions surrounding the CA1 pyramidal neurons in the striatum radiatum and striatum oriens of the CA1.…”

CD38 Knockout Mice Show Significant Protection Against Ischemic Brain Damage Despite High Level Poly-ADP-Ribosylation

“…Following the 10 min ischemic period, reperfusion was induced by reducing the isoflurane to 0 % and removing the CCA clamps. Then the animals were moved into a temperature-control incubator for about 3 h before they were moved into pre-heated cages for another 24 h [12, 13]. Animals in the sham group underwent the same surgical procedure without the occlusion of common carotid arteries.…”