Summary: Researchers believe that, given time, mitochondria can recover their normal form following TBI or stroke.
Source: Medical College of Georgia at Augusta University.
Cell powerhouses are typically long and lean, but with brain injury such as stroke or trauma, they can quickly become bloated and dysfunctional, say scientists who documented the phenomena in real time for the first time in a living brain.
The scientists also found that without giving these mitochondria anything but time, they often resume their usual healthy shape once blood and oxygen were restored to mild or moderately damaged tissue, said Dr. Sergei Kirov, neuroscientist in the Department of Neurosurgery at the Medical College of Georgia at Augusta University.
“We believe this is good evidence that mitochondria can recover their normal form following brief periods of ischemia from stroke or trauma and that drugs that enhance their recovery may improve overall recovery from these sorts of brain injuries,” Kirov said.
Even following a brief period of global ischemia, where the entire body is getting no oxygen like in cardiac arrest, mitochondria quickly recovered if blood and oxygen supplies were restored within five minutes. Three minutes longer and mitochondria did not regain their usual high-functioning lean state.
Previous studies in cultures of neurons and brain slices have provided evidence that form is
Kirov and Dr. Leonard Khiroug, neuroscientist at the Neuroscience Center at the University of Helsinki, Finland, are co-corresponding authors of the work in living brains published in the Journal of Neuroscience.
They used the power of two-photon laser scanning microscopy that enables long-term observation within living tissue coupled with transgenic mice with fluorescent mitochondria to document the cell powerhouses in the minutes, hours and days after mild, moderate and severe injury.
They focused on pyramid-shaped neurons in the cortex, the furrowed outer portion of the brain associated with higher cognitive function that is one of the first areas injured in stroke and traumatic brain injury. They looked specifically at mitochondria in these neurons’ dendrites, tree-like outgrowths with high-energy demands that are constantly receiving signals from other neurons. These typically also long and lean dendrites, which are jam-packed with mitochondria, become fragmented by these types of brain injuries. But the scientists saw the destructive mitochondrial transformation actually happened first and within minutes.
Kirov calls mitochondria dynamic structures that can maneuver around a dendrite to support the point of highest energy need at that moment. They also are connected to each other, much like power lines connect high-voltage electrical substations. Like most things in life, they also are double-edged swords that supply energy needed for cells to live and function but also can trigger cell death. Noxious events like a stroke or TBI could trigger that deadly signal.
One way they typically protect cells is by capturing calcium, an important signaling molecule in the brain that can be lethal at excess levels, which tend to occur with injury.
“When they become injured or fragmented, they cannot do these functions anymore,” Kirov said.
Mitochondria also can split and form new mitochondria to replace old ones, and part of the work ahead for the scientists is determining whether these are actually new mitochondria – rather than repaired ones – emerging particularly after a prolonged recovery from severe injury.
They also want to look at energy output of recovered mitochondria and existing drugs that might enhance that recovery. Of particular interest is the impact on the so-called penumbra, the brain area surrounding the focal point of a stroke or other brain injury, where injured brain cells might recover or die in the hours and days following the event.
Neurons and muscle cells are two of the biggest energy users and tend to have more mitochondria than other cell types. In a healthy brain scenario, if mitochondria happen to create too many new mitochondria, they will recycle them just like they do with old ones they replace.
Funding: The research was supported by the Academy of Finland, the Jane and Aatos Erkko Foundation and the National Institutes of Health.
Source: Toni Baker – Medical College of Georgia at Augusta University
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Reversible disruption of neuronal mitochondria by ischemic and traumatic injury revealed by quantitative two-photon imaging in the neocortex of anesthetized mice” by Mikhail Kislin, Jeremy Sword, Ioulia V. Fomitcheva, Deborah Croom, Evgeny Pryazhnikov, Eero Lihavainen, Dmytro Toptunov, Heikki Rauvala, Andre S. Ribeiro, Leonard Khiroug and Sergei A. Kirov in Journal of Neuroscience. Published online December 1 2016 doi:10.1523/JNEUROSCI.1510-16.2016
Reversible disruption of neuronal mitochondria by ischemic and traumatic injury revealed by quantitative two-photon imaging in the neocortex of anesthetized mice
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 such pathological conditions as stroke and brain trauma. Using in vivo two-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, while 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.
During ischemic stroke or brain trauma mitochondria can either protect neurons by supplying ATP and adsorbing excessive Ca2+, or kill neurons by releasing pro-apoptotic 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-time in vivo two-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.
“Reversible disruption of neuronal mitochondria by ischemic and traumatic injury revealed by quantitative two-photon imaging in the neocortex of anesthetized mice” by Mikhail Kislin, Jeremy Sword, Ioulia V. Fomitcheva, Deborah Croom, Evgeny Pryazhnikov, Eero Lihavainen, Dmytro Toptunov, Heikki Rauvala, Andre S. Ribeiro, Leonard Khiroug and Sergei A. Kirov in Journal of Neuroscience. Published online December 1 2016 doi:10.1523/JNEUROSCI.1510-16.2016