Controlling Aging At A Microscopic Scale? A New Quality Control Pathway For MitochondriaMay 2, 2016
Mitochondria, tiny organelles within our cells, pack a big punch. They function as powerhouses that generate energy for the cell. Malfunctioning mitochondria, explains Adam Hughes, assistant professor of biochemistry at the University of Utah, impacts a number of processes, such as aging and development of disease. He describes his latest research, published in eLife, discovering a never-before seen cellular structure dedicated to remodeling mitochondria that might be called into action in response to stress or other environmental cues.
Interviewer: Aging on a microscopic scale, up next on The Scope.
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Interviewer: I'm talking with Dr. Adam Hughes, Assistant Professor of Biochemistry at the University of Utah. Dr. Hughes, when I think of aging, I think about getting wrinkles, going gray, slowing down, but you think of aging on a different scale. How do you think about aging?
Dr. Hughes: We think about aging, I'd say, more at an organismal level or even more specifically than that, the cell biology level. Sort of looking at not how aging affects the whole organism, but how it affects specific structures within our cells within different tissues.
Interviewer: A lot of your research focuses on one component of the cell, an organelle called the mitochondria. First of all, can you orient us to the mitochondria? What does it do?
Dr. Hughes: Sure. Mitochondria, they're known as the powerhouse of the cell. Historically, they're drawn as kidney-bean-shaped structures you see in all the textbooks, but mitochondria do a lot of different things in metabolism. They're a double-membraned structure that produces lipids, they're involved in oxidative phosphorylation, they basically make energy for cells and also participate in a large number of metabolic reactions.
Interviewer: Studying the mitochondria is actually a whole field in and of itself. What's some of the evidence that mitochondria is involved in aging?
Dr. Hughes: Mitochondria has drawn a lot of attention, not only for its role in changes in mitochondrial function affecting how long an organism lives but it's also become very clear that as mitochondria become faulty with age, which happens for a number of different reasons in a number of contexts, this is also been linked to driving the development of a large number of age-associated disorders as well.
Interviewer: And as it turns out, there's quite an elaborate system for getting rid of or repairing mitochondria that does not function well. You've just published some research about this in the journal "eLife."
Dr. Hughes: I haven't explained much of what we've been doing. We've been using yeast as a model system to understand the aging process. So it's pretty cool that the single-celled eukaryote, the simplest one, and a lot of labs have been using it for a very long time to understand lifespan regulation type processes. And so our lab actually uses this organism in it does, in fact, age. A yeast cell, we measure aging by the number of times a cell can divide before it dies. Now, it happens about 30 times before a cell dies. And so in these old cells, it started several years ago when I was a postdoc at the hutch in Dan Gotchling's lab, we found it in old cells there was damaged or dysfunctional mitochondria.
So we decided to use this system to try to see what we can learn about how cells handle this, how they respond, what can they do. And we went into it, at the time, wondering if we could model pathways that were already known in mammals, one of the most prominent being the autophagy-dependent or self-eating pathways that had already been fairly well characterized. And so when we went into this, we set out to see in an old cell, do we see pieces of mitochondria? And we're visualizing all this on the microscope, being ripped off and degraded after they're damaged/
And we saw that there was, in fact, this going on in old yeast cells and so we initially thought it was similar to what had been observed already. And that's how we got into it. We didn't go into it looking for new pathways, but eventually it sort of, as we got more into the details of what this is going on, we realized they totally new type of quality control that we discovered that was different than anything else that had been described before.
Interviewer: So what is it? What did you find and how is it different from what was there, what you knew before?
Dr. Hughes: In general, in this field, it was always thought as a mitochondria became damaged that these systems aren't very smart for a lack of a better word, that they would go to the damaged mitochondria and just degrade the entire thing. Which seems a bit wasteful and so when we came into this we thought the same thing and we were using a protein on the mitochondria. We are monitoring it by microscopy and we could see that it was being eaten. But what we did that went beyond these original studies and other systems was there are about 1000 different proteins in the mitochondria. And we just started looking at other ones too. So most of the studies in mammalian cells had only looked at one or two and made conclusions.
And so we went on and looked at all mitochondrial proteins to see how they were all being degraded. What we discovered, based on this, and this is the big crux of this study, is that the pathway we've uncovered now is the concept and idea that mitochondria actually, under these situations when they're damaged, don't just get totally degraded as a whole. They can actually be broken down piece by piece. And what I mean by that is certain proteins can be basically selectively sorted out and removed from the mitochondria and degraded and the rest of it can be left intact.
Interviewer: Do you have any ideas yet of whether this pathway relates to aging or how it relates to aging?
Dr. Hughes: We got into it looking at aging, but we think it's actually going to have many applications in other systems, especially sort of metabolic-related disorders. We've been working from the standpoint of seeing the structure and it forms, it's sort of very descriptive. It forms, it gets released, it gets degraded and certain proteins go into it and certain ones don't. But understanding what the importance of it is and why it happens has been a much more difficult question. And we are starting to get at that.
We didn't get into a lot of it in this currently published paper, but some of our certain experiments are directed in the range of one thing that we did include here. And one big clue to us is the identity of the proteins that are actually degraded by the system. So again, the mitochondria has about 1000 proteins in yeast and when we looked at the proteins that are degraded by the system that we discovered, it's only about 10% of those proteins. And it turns out it's very selective for one particular group, which is a group of proteins called the mitochondrial nutrient carrier protein.
So the role of this group of proteins, there are about 30 of them, in the in the mitochondria, they basically facilitate the transport of all nutrients into and out of the mitochondria. So we're working from the fact that these are the main targets of this pathway and we think that giving us a big clue as to what might be its role. And so clearly, they're metabolite transporters. They're very heavily involved in all aspects of metabolism. And so we're testing the idea now, a hypothesis that this pathway may be very important for actually protecting mitochondria in times of changes in cellular metabolic state.
Interviewer: It's also kind of amazing to me that, especially in something as simple as a yeast, that there are still entire processes that we're still discovering.
Dr. Hughes: Yeah, I think that's definitely a really cool point. Sometimes, yeast in this day and age will get a bad rap. You hear all kinds of things that yeast research is done and things that we used to only be able to do in yeast, now we can do them in humans and other organisms. But what's sort of the big arena right now, I'd say, in the yeast field is cell biology. And it's been very limiting for a long time, the ability to look at all different proteins and all different things within the cell.
And what's really cool in the yeast field is that many, many years ago now, probably 10 years ago, a lab developed a collection of all yeast proteins tagged with a fluorescent protein, GFP. So it's about 6000 proteins in yeast. And so we have strains that contain every single one of them. And so there are a number of labs across the country, including ours, that are essentially using this collection to look at how the entire protium changes not in terms of levels, but in terms of localizations in cells.
And people are discovering a lot of new things that no one had ever noticed simply because we have the tools to do it now. And this is what's really nice in yeast. And we still don't have the ability to do this in mammalian systems yet. So I think the future will get there and we'll be able to start looking at these. But there's a lot of new, I'd say, cellular structures, cellular compartments that form under very particular conditions that people just hadn't seen before.
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