Interview With Mitochondrial Dysfunction Expert Prof. Thomas Schwarz

Throughout his career, Dr. Thomas Schwarz has studied the biological mechanisms that allow neurons to develop and function correctly. He received his AB and PhD at Harvard University. As a post-doctoral fellow at the University of California, San Francisco, he was part of the team that cloned the first potassium channel gene. Dr. Schwarz then joined the faculty of Stanford University where he combined genetic, electrophysiological and biochemical methods to study how ion channels (electrical gates of cells) and synapses (sites where cells communicate) function. He began studying mitochondrial dynamics when a gene mutation was identified that prevents mitochondria from being transported to synapses. Since becoming a professor of neurology at Boston Children’s Hospital and Harvard Medical School in 2000, his lab has focused on how organelles (structures within cells), especially mitochondria, move in neurons. His research on mitochondria also includes studies of neurodegenerative diseases, including Parkinson’s.

The research interests of the Schwarz Lab include 1) axonal transport of organelles, particularly mitochondria, by kinesins and dynein; 2) the development and structural plasticity of synapses; and 3) the trafficking of membrane proteins and exocytosis, particularly in neurons. His inquiries into these fundamental processes have brought him in contact with translational questions of neurodevelopmental disorders and neurodegenerative diseases. The etiology of Parkinson’s Disease and peripheral neuropathies have become a particular concern of his group.


picture of a mitochondria (wikipedia commons)


The following has been paraphrased from an interview with Prof. Thomas Schwarz on March 23rd, 2018.

(Click here for the full audio version)


Could you talk a little about the evolutionary history of mitochondria and how they came to be a part of who we are?

That is indeed fascinating, I think the more you learn about mitochondria the more you can get obsessed with them. Of course, no one was around a billion years ago to figure out exactly how it happened, but the idea is that they were once a free swimming separate organism that lived in close proximity to what would become our cells. This duo eventually became the type of eukaryotic cell found in all multicellular organisms. Eukaryotic cells are those that have a cell nucleus and other organelles enclosed within the cell’s membranes. They make up everything in our body. The mitochondria at one point had such a close symbiotic relationship that they actually entered into the cells. The cells became dependent on the mitochondria to provide them with ATP and the mitochondria became dependent on the rest of the cell to provide them with the nutrients that they needed to make ATP. This ancient collaboration got to the point that one could not live without the other.

There are lots of signatures within the mitochondria that let us know that they were once separate bacteria-like organisms. They have their own DNA, their own ribosomes, and their own transfer RNAs just like bacteria out in the wild have.

How did our cells produce energy before we merged with mitochondria?

We have a pretty good idea about that. There is a process in the body called fermentation, which is how a lot of bacteria make energy. In that process they consume glucose and then break it down in a few easy steps to get a small amount of ATP yield from each molecule of glucose that the cell takes up. It’s a process that doesn’t require oxygen but is not enormously efficient. The other way of getting energy is a process called respiration. If you think about it, the only reason that you and I breathe is because our mitochondria need oxygen to go through this biochemical process where the sugar essentially gets burnt and the energy released gets converted into ATP.

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.

Are mutations in the PD associated genes Pink1 and Parkin the best measure that we have of mitochondrial health? 

I would phrase it differently; I would say that those are two of the proteins that most directly point to the fact that problems in mitochondrial health can give rise to Parkinson’s. Those two proteins are part of the system by which mitochondria get consumed and delivered to the trash collector systems of the cell.

We can judge mitochondrial health in a lot of ways. One is by asking how good a job it is doing of pumping protons out of the mitochondria, because it is by pumping protons out that it later will allow protons to come back in, which drives the pump that makes ATP. So the gradient of protons across the membrane is one way of judging mitochondrial health. As sugar gets consumed and oxidized, it isn’t used directly in making ATP, it gets used to push hydrogen ions (protons) across the membrane of the mitochondria. It’s like pumping water up stream against a damn, there is a lot of potential energy stored in the water in the damn, then by letting the water run out through a turbine you can generate electricity. The mitochondria pump the protons out of themselves, across their inner membrane, and then let the protons run back into the mitochondrion, through something that looks a lot like a turbine, and that produces ATP.

Another way of measuring mitochondrial health is asking how much oxygen they are using up. If you have cells in a dish, I can give them glucose and ask how much oxygen are they consuming, just like if you light a match in a room you can measure the difference in oxygen level before and after to determine how much oxygen the match consumed.

Another way is by looking at the mitochondrial DNA and checking for errors or deletions. As we get older all of our DNA pick up mistakes, so does mitochondrial DNA.

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.

Are there any diets and supplements that would allow us to optimize the health of our mitochondria? 

To me it is not obvious that there would be supplements that would do that. For me the greatest hope would be in things that are scavengers of reactive oxygen species (ROS). Keeping ROS at low levels would decrease damage to mitochondrial proteins and get them to live longer. The trouble with that is that the mitochondria are the place where ROS are made, so if you have a chemical to react with them, a sort of vacuum cleaner to mop them up, you would need it right there at the mitochondria for it to work. Which is very tough, but I am not saying that it is not an avenue worth pursuing, but I think we need solid evidence that it’s beneficial before we put too much faith in it.

What effects does exercise have on mitochondrial health?

We know that in muscles, the more you exercise the more mitochondria your muscles make. The link between exercise and muscle mitochondria is really good. But, the link between exercise and mitochondria in our brains is not so clear. I have not seen any evidence that it was really affecting mitochondria in the parts of the brain that we care about. On the other hand, exercise is good for you regardless so we should all get out there and do it.


Click here to learn more about the work of Prof. Thomas Schwarz


  1. Have you looked into the possibility that advanced glycation end products are produced as part of respiration? Perhaps even inside the mitochondria and exercise may be effective in stimulating the lymph and glymphatic systems to flush them out of the body?

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