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 2h recovery with mitochondria in CA1 becoming progressively more fragmented during the 24h recovery period. Mitochondria in CA3 and dentate gyrus neurons started to re-fuse after 24h of recirculation; this was even more pronounced 3days after ischemia. Astrocytic mitochondria underwent transient fission 2h after ischemic insult and regained their normal shape at 24h 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.