ARVO 2025: OPA1 mutation's effect on retinal ganglion cells' electrical function

At ARVO 2025, in Salt Lake City, Utah, Steven Barnes, PhD, talked about his research on the OPA1 mutation in retinal ganglion cells' effect on the cell's electrical function.

Video Transcript:

Editor's note: The below transcript has been lightly edited for clarity.

Steven Barnes, PhD:

Hi, I'm Steve Barnes. I have a PhD in retinal neurobiology, and I'm a professor at UCLA, working at the Doheny Eye Institute. I've been to about 20 ARVO meetings over the decades, and it's always been great, and it's always exciting to bring your latest discoveries in research to the meeting. The project we're presenting at ARVO is about human stem cell-derived retinal ganglion cells, the cells that die in diseases such as glaucoma and many other optic neuropathies. We took advantage of a colleague that I have at UCLA; I've worked with her for about a decade, Dr Xian-Jie Yang, and she produced some of these retinal organoid-derived ganglion cells that are human–they come from the patients of one of the Doheny doctors, Dr Alfredo Sadun. And he's a wonderful guy to work with. Basically, Xian-Jie Yang provided us with these retinal ganglion cells that are from Dr Sadun's patients that have a genetic mutation called OPA1, and it leads to blindness by causing the death of retinal ganglion cells.

Our role and what we're interested in doing, since we're electrical engineers, basically, of the retina, was to analyze what this mutation does to the function of retinal ganglion cells, namely, its electrical function. Ganglion cells communicate with the brain by sending electrical signals to the brain; these are called action potentials. The OPA1 mutation affects the mitochondria. Those are the energy-producing factories that all cells have in them, and so typically they don't function properly, and basically that means they don't make enough energy that the ganglion cells need, or any of the cells in the body. Ganglion cells, it turns out, are extremely energy-expensive cells, and they're the ones that come up with difficulty in their function early in a situation like this. Our goal was to show the difference in ganglion cell electrical function, how it makes action potentials between OPA1 mutant cells and control human cells. So that was the goal, and that's what we did.

We came up very quickly with a remarkable finding. We found that the spiking activity of the OPA1 mutant cells was really different than the control cells, normal cells. And we are able to really take the cell's electrical activity apart using something called a voltage clamp and study how does the electricity in the cell really work? We know very well how action potentials work, so it's an easy job to go in, break it apart into sodium channel activity and potassium channel activity to understand the action potentials. It was very clear that in the OPA1 mutant cells, they had twice as much potassium channel currents. Which is an enormous amount. And it struck us that this has something to do with the energy level of the cell that is run amok in this OPA1 mutation. The enormous amount of extra potassium current suppresses the cell's activity. They end up changing their spike frequency, how rapidly they produce these action potentials, dramatically. We can't say what part of that activity is damaging to the cell, but it is a clear signal the cell has built-in systems to try to stop difficulty that it's going to face, and one of those is to have ion channels that are capable of detecting low energy states that are caused by a defective mitochondria. They do that by measuring how much ATP is in the cell; the channels manage to sense this chemical, and that is the chemical that brings the energy to the cells. So when they find in the cells with that mutation, the ganglion cells produce lower ATP levels in the cell, that leads to these channels, these potassium channels, sensing the low ATP and in turn are becoming more active, which means they cause an energy-saving state to start in the cell. So they're trying to help the cell survive this problem that the defective mitochondria are causing.

It seems like this is something if we could model this sufficiently and be able to control that in ganglion cells, it could be a really neat way to actually help patients' eyes and not have them become blind by lowering the energy needs of their cells, partly by having these extra potassium channels. Ganglion cells, as I said, are extremely energy sensitive. They use a lot of energy, and if the energy goes even slightly down, they can become defective. All cells in the body are struggling with the same mutation. So to some degree, all cells in the body are undergoing metabolic stress, so that could affect many different functions of the human body.

We entered this with no expectation of what we were going to find electrophysiologically in the ganglion cells. We found it immediately. So it was pretty exciting. And then our goal was, why are the ganglion cells spiking differently? And we dug in, voltage-lamped the cells, and figured it out actually, very rapidly. There's much more research to do on this, but we're extremely excited to have discovered a new ATP-sensitive, delayed rectifier potassium channel in retinal ganglion cells. It's very exciting for me to have, quote-unquote, discovered a new ion channel. And I'm stunned. By the way, we've also found it in mice. But it's just really rewarding to jump in and find this, which it's almost—I couldn't believe it. We will pursue this. We have our goal, really: how can we control this? Can we use this system to make the cells survive better and prevent the dramatically bad events that happen to the cells, causing their death?