Dementia has impacted many lives with the most common cause being Alzheimer’s disease. In a paper published in 2018 scientists identified a crucial link between calcium uptake by mitochondria and neurodegenerative diseases such as Alzheimer’s, Huntington’s and Parkinson’s disease. Could this hold the key to preventing dementia?
If you can remember anything from your biology lessons at school it’s that mitochondria are the powerhouse of the cell. Mitochondria are tiny organelles found within each and every animal and plant cell. Their main function is to provide the cell with energy but they also have roles in cell signalling and cell death.
Within the cell calcium ions act as tiny messengers in signalling pathways to help the cell coordinate gene activation, cell division and cell death.
When not needed calcium can be stored in an internal store within the cell such as within mitochondria. This means mitochondria have the ability to release and store calcium so can either trigger or prevent messages passing through the cell.
Imagine a single calcium ion as a homing pigeon - the birds used to carry letters during the war. You need to send a message to the other side of the world (the cell) so decide to use a pigeon. However, during its voyage the pigeon is caught and trapped (by mitochondria) so the message never reaches the receiver.
If the mitochondria dysfunction this interception of the message can go wrong - too many or too little pigeons are trapped. The receiver either doesn’t get the message at all or there is an overload of messages and it doesn’t know what to do.
What can the cell do about this? Ultimately, nothing.
The cell cannot coordinate vital processes and respond to meet changes in their energy demand. For example, mitochondria themselves require calcium to help activate their enzymes used to generate energy. Therefore, if mitochondria take up too little calcium their enzymes aren’t activated and they can’t produce enough energy to power the cell so the cell will die.
In contrast, if a mitochondrion takes up too much calcium there can be an overload and the surplus of calcium induces the opening of a pore within its membrane. The gates open and in comes a flood of the cell’s cytoplasm until, eventually, the mitochondrion will burst releasing its contents into the cell. This means toxic molecules are released into the cell which helps trigger cell suicide (intrinsic apoptosis).
So, either way (be it due to taking up too much or too little calcium) mitochondrial dysfunction is almost always fatal for the cell - and if cells die the organism has a big problem.
Neurodegenerative diseases such as Alzheimer’s, Huntington’s and Parkinson’s disease are characterised by deterioration and loss of function of the nervous system. The main cause of this is through the death of neuron cells which, as explained previously, can be due to mitochondrial dysfunction.
Small molecules such as calcium can travel freely between mitochondria and the cell cytoplasm through tiny channels (voltage dependent anion channels) within mitochondria’s outer membrane. Therefore, the more channels there are the more calcium can enter the mitochondria, causing an overload and ultimately cell death.
A research group in Israel identified that in cells affected by Alzheimer’s disease there were high levels of these tiny channels. This means more calcium could enter their mitochondria and more toxic molecules could be released into the cell compared to healthy cells.
As a result, the neuron cells die quicker leading to memory loss and personality changes, which are typical characteristics of neurodegenerative diseases. Therefore, an obvious target to prevent these diseases is to prevent the death of neuron cells by stopping mitochondrial dysfunction.
However, since mitochondria are located inside cells themselves they’re extremely difficult for scientists and drugs to access, meaning treatments are not straightforward. For example, for drugs to have an effect on mitochondria they have to enter the cell first but in most cases very little of the drug makes it that far and it causes many side effects.
So, if the mitochondria can’t be reached by drugs can the cell be reprogrammed to have mitochondria that function normally?
Unfortunately, no. Mitochondria contain their own DNA that isn’t kept within the nucleus of the cell so gene editing techniques such as CRISPR that target the nucleus will not work.
Because mitochondrial DNA isn’t located in the nucleus, when the male and female nuclei fuse together during fertilisation the mitochondria aren’t affected. This means an individual's mitochondria are inherited directly from the mother only. Therefore, if your mother has a neurodegenerative disease you will likely inherit it - if it’s cause was mitochondrial dysfunction.
Of course, there are treatments already available for people affected by these diseases but imagine if scientists do find an effective way to prevent mitochondrial dysfunction - it will help thousands!
Some day we may be able to prevent diseases like Alzheimer’s, Huntington’s and Parkinson’s, and help to reduce the huge number of people who will one day be affected by dementia.
For me, this is what pursuing a career in biochemistry is all about. Delving deep into scientific research to decipher how something works, then applying it to something bigger that has the potential to help so many people - just like those scientists did in Israel.
One day I want to be like those scientists.
I came across the scientific paper this post was based on while researching for a presentation for a series of tutorials based on calcium signalling. The presentation content was then adapted for an assessed essay which focused on the relationship between mitochondria and calcium, and the biochemistry involved.
Shoshan-Barmatz, V. et al. (2018). VDAC1, mitochondrial dysfunction, and Alzheimer's disease. Pharmacological Research, 131, 87-101.
**Image by Bret Kavanaugh on Unsplash**
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