Reversible Disruption of Neuronal Mitochondria by Ischemic and Traumatic Injury Revealed by Quantitative Two-Photon Imaging in the Neocortex of Anesthetized Mice
| Autor: | Andre S. Ribeiro, Jeremy Sword, Mikhail Kislin, Leonard Khiroug, Eero Lihavainen, Dmytro Toptunov, Sergei A. Kirov, Heikki Rauvala, Ioulia V. Fomitcheva, Evgeny Pryazhnikov, Deborah Croom |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Pathology medicine.medical_specialty Dendritic spine Mice Transgenic Neocortex Biology Mitochondrion Neuroprotection Brain Ischemia Brain ischemia Lesion 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Anesthesia Fragmentation (cell biology) Research Articles Fluorescent Dyes Neurons General Neuroscience Dendrites medicine.disease Mitochondria Mice Inbred C57BL 030104 developmental biology Traumatic injury Microscopy Fluorescence Multiphoton Apoptosis Brain Injuries Female medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 37(2) |
| ISSN: | 1529-2401 |
| Popis: | Mitochondria play a variety of functional roles in cortical neurons, from metabolic support and neuroprotection to the release of cytokines that trigger apoptosis. In dendrites, mitochondrial structure is closely linked to their function, and fragmentation (fission) of the normally elongated mitochondria indicates loss of their function under pathological conditions, such as stroke and brain trauma. Usingin vivotwo-photon microscopy in mouse brain, we quantified mitochondrial fragmentation in a full spectrum of cortical injuries, ranging from severe to mild. Severe global ischemic injury was induced by bilateral common carotid artery occlusion, whereas severe focal stroke injury was induced by Rose Bengal photosensitization. The moderate and mild traumatic injury was inflicted by focal laser lesion and by mild photo-damage, respectively. Dendritic and mitochondrial structural changes were tracked longitudinally using transgenic mice expressing fluorescent proteins localized either in cytosol or in mitochondrial matrix. In response to severe injury, mitochondrial fragmentation developed in parallel with dendritic damage signified by dendritic beading. Reconstruction from serial section electron microscopy confirmed mitochondrial fragmentation. Unlike dendritic beading, fragmentation spread beyond the injury core in focal stroke and focal laser lesion models. In moderate and mild injury, mitochondrial fragmentation was reversible with full recovery of structural integrity after 1–2 weeks. The transient fragmentation observed in the mild photo-damage model was associated with changes in dendritic spine density without any signs of dendritic damage. Our findings indicate that alterations in neuronal mitochondria structure are very sensitive to the tissue damage and can be reversible in ischemic and traumatic injuries.SIGNIFICANCE STATEMENTDuring ischemic stroke or brain trauma, mitochondria can either protect neurons by supplying ATP and adsorbing excessive Ca2+, or kill neurons by releasing proapoptotic factors. Mitochondrial function is tightly linked to their morphology: healthy mitochondria are thin and long; dysfunctional mitochondria are thick (swollen) and short (fragmented). To date, fragmentation of mitochondria was studied either in dissociated cultured neurons or in brain slices, but not in the intact living brain. Using real-timein vivotwo-photon microscopy, we quantified mitochondrial fragmentation during acute pathological conditions that mimic severe, moderate, and mild brain injury. We demonstrated that alterations in neuronal mitochondria structural integrity can be reversible in traumatic and ischemic injuries, highlighting mitochondria as a potential target for therapeutic interventions. |
| Databáze: | OpenAIRE |
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