Reactive Structural Dynamics of Synaptic Mitochondria in Ischemic Delayed Neuronal Death

Abstract

The effect of transient global ischemia on the ultrastructural features of synaptic mitochondria at the distal dendrites of CA1 hippocampal neurons was investigated in 3-month-old rats. Sham surgery was performed on age-matched controls. The number of mitochondria/microm3 of neurophils (Nv: numeric density), the mitochondrial average size (average volume: V), and longer diameter (Fmax) as well as the overall fraction of neurophils occupied by mitochondria (volume density: Vv) were measured by computer-assisted morphometry. In ischemic rats, a 10% nonsignificant decrease of Nv was found, V increased nonsignificantly by 11%, and Fmax increased nonsignificantly by 5% versus controls. As a final outcome of these balanced changes, Vv remained unchanged between the two experimental groups investigated. In ischemic animals, the percentage distribution of V showed that the population of CA1 synaptic mitochondria was composed by an increased fraction of oversized organelles, while the Fmax distribution revealed that this enlargement was due to an increased percentage of elongated organelles. Thus, the observed increase in size should not be considered as a swelling phenomenon; on the contrary, it may represent a physiological and well-documented step in mitochondrial biogenesis. The above parameters are currently supposed to provide information on the adaptive structural reorganization of mitochondrial morphology under different environmental stimulations. Conceivably, these findings document a positive reactive response to ischemia of the mitochondrial structural dynamics at CA1 synaptic terminals and suggest consideration of these organelles as reliable targets in the development of neuroprotective therapeutic interventions to treat vascular brain diseases, for example, stroke.

Sex differences in mitochondrial biogenesis determine neuronal death and survival in response to oxygen glucose deprivation and reoxygenation

“…Histological evidence of mitochondrial biogenesis was found after transient global ischemia in adult rats [39]. We found enhanced expression of PGC-1α, Tfam and NRF-1 mRNA, and PGC-1α and TFAM protein levels in XY neurons in comparison to XX neurons.…”

Rapidly Increased Neuronal Mitochondrial Biogenesis After Hypoxic-Ischemic Brain Injury

“…The evidence for this occurring in cerebral H-I models is not clear and has been examined in only a few studies using adult ischemic models. For example, increased mitochondrial elongation, a well documented step in the process of mitochondrial biogenesis, was observed in the CA1 region of the hippocampus after transient global ischemia in adults 9,11. Histological evidence of mitochondrial biogenesis was also found after transient global ischemia in adult rats 11.…”

“…For example, increased mitochondrial elongation, a well documented step in the process of mitochondrial biogenesis, was observed in the CA1 region of the hippocampus after transient global ischemia in adults 9,11. Histological evidence of mitochondrial biogenesis was also found after transient global ischemia in adult rats 11. In transient focal ischemia, 30 minutes of ischemia induced a reduction in mtDNA content; however, mtDNA was restored to nearly preischemic levels 24 hours later 13.…”

“…The evidence in support of cerebral mitochondrial biogenesis after neuronal injury is incomplete, as no study has definitively measured an increase in the number of mitochondria after neuronal injury 8–11. Furthermore, mitochondrial biogenesis has never been studied in neonatal hypoxic H-I.…”

Novel Mitochondrial Targets for Neuroprotection

“…Transient increases in mitochondrial proteins and mtDNA can be induced by ischemic injury, including neonatal hypoxia/ ischemia (Rasbach and Schnellmann, 2007;Yin et al, 2008). Furthermore, modest changes in mitochondrial mobility and morphology were also observed in neuronal ischemia (Bertoni-Freddari et al, 2006;Yin et al, 2008;Valerio et al, 2011). The calcium-and oxidant-sensitive nature of several of the signaling molecules leading to mitochondrial dynamics underscore the need for further investigation of the role of mitochondrial responses as an organelle after neural ischemic injury.…”