Targeting 'Powerhouses' of Brain Cells Could be a New Treatment Strategy for Stroke

Highlights

• Mitochondria supplies the energy needed for cells to live and function and also trigger cell death or apoptosis.
• Their function depends on their shape, where healthy mitochondria are long and lean and dysfunctional mitochondria are thick and fragmented.
• Stroke or brain injury leads to fragmentation of mitochondria, following which they fail to perform their protective functions.
• New study states that mitochondria can be a potential target for therapeutic interventions following stroke or brain injury.

Cell powerhouses or mitochondria are typically long and lean, but with brain injury such as stroke or trauma, they can quickly become bloated and dysfunctional. The scientists led by Dr. Sergei A. Kirov, neuroscientist in the Department of Neurosurgery at the Medical College of Georgia at Augusta University, documented the phenomena in real time for the first time in a living brain.

Up until now fragmentation of mitochondria was studied either in dissociated cultured neurons or in brain slices.

Neurons and muscle cells have more mitochondria compared to any other cells in the body because they are two of the biggest energy users.

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.

Following a brain injury or events like cardiac arrest which is considered as global ischemia, where the entire body is deprived of oxygen, the mitochondria often resume their long and lean shape with time once blood and oxygen are restored to mild or moderately damaged tissue.

But the supply of oxygen or blood should be within 5 minutes following the incident. If the delay occurs by extra three minutes, mitochondria does not regain their usual high-functioning lean state.

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"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.

Mitochondria functions by either protecting neurons by supplying ATP (adenosine triphosphate) and adsorbing excessive calcium ions, or killing neurons by releasing pro-apoptotic factors.

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Mitochondrial function is tightly linked to their morphology:

• healthy mitochondria are thin and long
• dysfunctional mitochondria are thick (swollen) and short (fragmented)

Fragmented Mitocondria

Mitochondria are dynamic structures that are connected to each other and can maneuver around a dendrite to support the point of highest energy need at that moment.

They supply energy needed for cells to live and function but can also trigger cell death or apoptosis.

Mitochondria protect cells is by capturing calcium, an important signaling molecule in the brain and supplying ATP (adenosine triphosphate).

During a brain injury mitochondria become injured or fragmented and trigger deadly signals.

They cannot perform protective functions of capturing calcium anymore. This may result in excess levels of calcium which can be lethal and lead to cell death.

Studying the 'Powerhouses' in Real-Time

Researchers studied the fragmented mitochondria in transgenic mice with brain injury.

They used two-photon laser scanning microscopy to document the cell powerhouses in the minutes, hours and days after mild, moderate and severe injury.

One of the first areas to be affected by stroke or brain injury is the cortex, which is associated with higher cognitive functions.

The cortex has pyramid shaped neurons with long and lean dendrites. They constantly receive signal from other neurons and are packed with mitochondria.

During a stroke or injury, these neurons become fragmented and the researchers discovered that the destructive mitochondrial transformation actually happened first and within minutes.

So intervening at the mitochondrial level within a short duration following a stroke or brain injury may aid in recover.

Work Ahead for Researchers

Mitochondria can split and form new mitochondria to replace old ones. As part of recovering from severe injury, scientists need to determine whether these are actually new mitochondria emerging after a prolonged recovery from severe injury or if they are repaired ones.

Researchers also want to look at energy output of recovered mitochondria and existing drugs that might enhance that recovery.

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.

Reference

1. Sergei A. Kirov et al. Reversible disruption of neuronal mitochondria by ischemic and traumatic injury revealed by quantitative two-photon imaging in the neocortex of anesthetized mice. Journal of Neuroscience ; (2016) DOI: https://doi.org/10.1523/JNEUROSCI.1510-16.2016

Source-Medindia