An Interview on Mitochondrial Decline in Aging and Neurodegeneration
In this interview, a researcher focused on mitochondrial biochemistry discusses the role of these important cellular structures in aging and neurodegeneration, particularly Parkinson's disease. There are really two ways of looking at mitochondria in aging. The first, the view incorporated into the SENS program, looks at damage to mitochondrial DNA and its consequences. A small but significant number of cells fall into a dysfunctional state because some forms of randomly occurring mitochondrial DNA damage can replicate rapidly within the cell, leading to cells that pollute their surroundings with reactive, harmful molecules. This might be addressed by providing backup copies of mitochondrial genes, a methodology known as allotopic expression.
The second view looks at mitochondrial dynamics and morphology, both of which change considerably in response to differences in the environment between old cells and young cells, old tissues and young tissues. This is a much more complex problem to consider, as no-one has yet mapped the chains of cause and effect that stretch from the fundamental forms of damage at the root of aging to this downstream manifestation of aging. Nor is it entirely clear how to best go about reversing these changes - not to mention whether or not some are adaptive to the damaged environment, protective rather than the cause of even more harm.
How many mitochondria are there within each dopamine producing neuron and how frequently are they created?
The dopaminergic neurons in the pars compacta of the substantia nigra, the ones most related to Parkinson's disease, have enormous axons. If you add up all the branches, it is estimated that you would have several meters of axon coming from each cell. If you take the density of mitochondria in a segment of axon, you can then calculate what the total would be. The number is roughly two million mitochondria in each neuron. That's two million mitochondria frantically consuming oxygen and making ATP, all to keep that one cell alive.
On top of that, the proteins in the mitochondria are not going to stay stable for the 80 to 100 years that we live for. The proteins start to fall apart because of heat and the environment they are in. It turns out the mitochondria are a particularly dangerous place for a protein to be, because the mitochondria, in the process of its respiration, generate reactive oxygen species (ROS) which collide with proteins and chemically alter and damage them. Proteins everywhere in the cell have to be constantly degraded and replaced; in a mitochondrion that is even more true because the proteins get damaged even faster.
So we did a back of the napkin calculation, and asked how many mitochondria that cell would have to create every day in order to keep its two million mitochondria healthy and happy? The answer is something like thirty thousand mitochondria created every day. Most of the cells in our body don't have this problem, skin cells and liver cells are tiny and don't need nearly as many mitochondria. That could be part of the reason why, when something is wrong with our mitochondria, it is our neurons that suffer first, particularly the biggest neurons.
Does all that explain why, in Parkinson's disease, these neurons die and not other neurons?
Well, we don't know for sure yet what makes one cell more sensitive than another, but I think that is an excellent guess. The fact that those nerve cells fire at a very high rate, and that every time they fire it opens up a particular type of calcium channel that lets a lot of calcium in, means that you are going to need a lot of ATP to pump that calcium back out of the cell, as well as pumping sodium and other things. That puts a very strong demand on the cell. Then the fact that it has so many branches and so many synapses on the end of it also means that you are going to need a lot of energy to power those synapses. It is indeed a very energy hungry type of nerve cell, and nerve cells are the most energy hungry type of cell in the body. So it has this dual problem of supplying enough mitochondria and then putting strain on the mitochondria to travel through the axons and pump out enough ATP.
Which therapies that target mitochondrial health are you most hopeful for?
I think there are four ways to try to approach it. If you can figure out what is damaging the mitochondria and stop the damage that would be a great thing. In some cases antioxidants might do that. In cases where there are environmental toxins, like paraquat or rotenone, getting those out of the environment is definitely going to help. But in the case where there is a genetic mutation, you can increase the rate at which damaged mitochondria are removed and hope that the cell compensates by increasing the rate of production of healthy ones. There are also genes that control how mitochondria replicate and how they get new proteins added to them, if we can figure out how the cell controls the number of mitochondria and increase that number, that could improve the health of the cell.
Finally, the one that I am most interested in is the transportation problem. It is one thing to try and get proteins into the mitochondria in the cell body, but that cell body is just a tiny fraction of the volume of the neuron, way less that 1% of the cell. The cell has to somehow get mitochondria all the way out to the periphery of the cell and through all of its many axons. Improving the delivery of mitochondria into the remote regions of the cell should also improve the health of the cell.