Lemons from Lemonade: Recycling Reactive Oxygen Species

Way back in high school bio, I learned about the 2 main ways that eukaryotic organisms (everything other than bacteria and archaea) make their metabolic living: photosynthesis and oxidative phosphorylation (also known as respiration). These two processes are fundamentally related - photosynthesis combines CO2 and water to produce sugar and oxygen, while respiration breaks down sugars using oxygen, leaving water and CO2. But the cells of plants, animals and fungi can't do either of these things on their own. Sometime in our distant evolutionary past, we took on tiny passengers that do the work for us.

As Heather wrote yesterday about chloroplasts,

Some photosynthetic bacteria eons ago found itself nestled inside another cell, realized it was a pretty sweet place to call home, and viola - a new cell organelle was born. OK fine, that is a bit of an oversimplification. The endosymbiotic theory is a bit more complicated, but that's the general idea.

And it's the same general idea for mitochondria, which perform respiration. As you probably know, only plants have chloroplasts (until the Harvard scientists Heather mentioned have their way), but ALL eukaryotes have mitochondria. It's possible to get energy from sugar without oxygen, but it's not very efficient. Our mitochondria extract over 10 times as much energy from a single molecule of glucose than would be possible without them. But all that efficiency comes with a price - a byproduct of respiration is "reactive oxygen species" or ROS (no, not ROUS).

Yet, as with so many things in evolution, a cell sees lemons and decides to make lemonade:

ResearchBlogging.orgTLR signalling augments macrophage bactericidal activity through mitochondrial ROS

Reactive oxygen species are, as you might have guessed, reactive. They can cause all kinds of damage to proteins and lipds, and even DNA. Evidently, macrophages have learned to harness this destructive power to their advantage, by shuttling the ROS produced by mitochondria into the phagosomes that contain bacteria.

For a long time, researchers have known that macrophages use ROS to cope with bacterial invaders. There are enzymes like inducible nitric oxide synthase (iNOS) and NADPH oxidase that intentionally make ROS to deal with bacteria. But A West et al have now shown that macrophages can divert the waste stream from mitochondria, recycling these destructive molecules for their bacteriacidal activity.

First, they hit macrophages in cell cuture with a few related stimuli - some activate bacteria-sensing TLRs, some hit virus-sensing TLRs, and some are just general activators. They found that mitochondrial ROS (mROS) increased in response to bacteria-related signals, but not to the others. In the plots below, the doted lines represent the stimulated cells, while the solid lines show control cells. Lines further to the right indicate more mROS.

i-16d014d81e5c3328fea39911db40750d-Screen shot 2011-05-09 at 12.48.36 PM.png

They also showed that mitochonrial membranes associate with phagosomes containing latex beads coated with TLR ligands, but not the beads themselves. These images show macrophages stained with an antibody that makes a mitochondrial membrane protein fluoresce green. The beads are red, and the places that they localize together are in yellow in the bottom panels.

i-2cf24979ceac7d8dcdea6e3e5e5580c4-Screen shot 2011-05-09 at 12.48.52 PM.png

They also did some biochemistry showing parts of the TLR signaling pathway interacting directly with mitochondria. But the most convincing experiment is in the last panel. Here, they use salmonella to infect mice that over-express an enzyme called catylase in their mitochondria (MCAT). Catylase is one of the enzymes that normal cells use to protect themselves from rogue ROS - it helps convert them into harmless molecules, and these mice generally live longer and show less age-related oxidative damage. However, this decrease in mitochondrial ROS severly impaired the macrophages' ability to deal with bacterial infection. After 5 days, these mice had over five times as many bacteria in their spleen than wild-type mice.

i-39b6c3d4f681c6b1a35e456fffff1395-Screen shot 2011-05-09 at 12.49.25 PM.png

I'm not sure if there are any direct health implications of this work (maybe antioxidants aren't all they're cracked up to be), but I think it's a cool example of evolution making the best out of a bad situation.

West, A., Brodsky, I., Rahner, C., Woo, D., Erdjument-Bromage, H., Tempst, P., Walsh, M., Choi, Y., Shadel, G., & Ghosh, S. (2011). TLR signalling augments macrophage bactericidal activity through mitochondrial ROS Nature, 472 (7344), 476-480 DOI: 10.1038/nature09973

More like this

A lot of people think of viruses and bacteria in our bodies as nothing more than pests. It's certainly true that a lot of them do an excellent job of making us ill. But some viruses and bacteria merged with our ancestors over the course of billions of years, and if you were to have them removed…
Second lecture notes from my BIO101 class (originally from May 08, 2006). As always, in this post and the others in the series, I need comments - is everything kosher? Any suggestions for improvement? --------------------------------------------------- BIO 101 - Bora Zivkovic - Lecture 1 - Part 2…
At Billy Dembski's blog, Granville Sewell wonders What if we DID find irreducibly complex biological features?: In any debate on Intelligent Design, there is a question I have long wished to see posed to ID opponents: “If we DID discover some biological feature that was irreducibly complex, to your…
I feel like I've seen this movie before. A group of thieves need to gain entry to a highly secured vault. The vault door is nearly impregnable, and once inside, there are motion sensors, security cameras and laser trip lines, all of which sound the alarm. When the security guards hear what's…

So, ROS helps to fight certain types of bacterial infection. It would seem that although oxidation adds to the aging process it can be an adaptive reaction to bacterial infections. To be frank the clarity of my understand could be described as murky. However, a couple of things come to mind: Nick Lane(you've mentioned him here before) in his book, "Power, Sex Suicide..." discusses the movement increase levels of anti-oxidents maybe misguided for a variety of reasons...This would seem to support a similar sort of theory. The other thing is sickle cell anemia. Meaning that having the disease can be seen as maladaptive because it leads to death at an early age...however, if you live in a malaria prone area having it as a recessive trait means a lower liklihood of contracting malaria and thus living longer. In the case of sickle cell the situation is entirely genetic and effective against a parasitic response. In the case of ROS it appears to be a response to a bacterial infection. In one case having sickle cell traits can lead to a shorter life...or having ROS can lead to a shorter lifef...but both can lead to greater survivability against other organisms. Feel free to correct any errors of fact or insight as I'd like to have a much greater understanding than I do...

By Mike Olson (not verified) on 11 May 2011 #permalink

Mike - There's a difference between these two cases, but they're in the same ball-park. Generally speaking, traits can persist in populations for a number or reasons. You're spot-on for the reason (we think) the sickle cell allele managed to persist. Heterozygosity (having one good copy and one mutant copy) is a huge benefit, and probably out weighs the loss of fitness that comes from offspring having full-blown sickle-cell disease.

The case of ROS is a bit more complicated. Using respiration for metabolism has the down-side of generating reactive oxygen species, but this down side is more than made up for by the boost in efficiency. We can get over ten times as much energy out of a single molecule of glucose if we use oxygen to break it down. The production of mitochondrial ROS did not evolve for the purpose of fighting microbes, it evolved because it's a necessary side-effect of oxygen metabolism. But evolution found a way to re-purpose that negative side effect in the service of something beneficial (and as I mentioned, intentional ROS production in the service of killing microbes did evolve, as there are enzymes expressed in phagosomes that use energy to make ROS on purpose).

Metabolic pathways or sequences take place in small increments. This prevents potential damage to cells if too much heat energy was liberated all at once. These small steps increase overall efficiency and make it easier to control the processes. It also creates many more sites where interruptions can have an impact on a reaction.

Thank you. You're right, that is a very basic, essential difference I didn't consider. Your title is then on the money. The process is necessary to most efficiently provide energy, but that creates a potentially damaging by-product, but a use is found for that by product. A use that never would have been available if not for the initial process. It would be like finding a use for CO2 output in cars.

By Mike Olson (not verified) on 12 May 2011 #permalink

CO not CO2

By Mike Olson (not verified) on 12 May 2011 #permalink

Hello friends -

Very neat post.

In a somewhat related vein, some here might be interested in knowing that there is also evidence that ROS might be an important signalling mechanism in things like exercise.


Personally, I am considering using this knowledge as a reason to stop drinking vodka/acai/lemonades after working out and just moving to straight martinis. For science's sake.

- pD

Omg!! What a great idea a million thank you's!!! You just saved me so much money!! I thought this was going to have to be a when we "get a chance project"!! But now so excited because we can do in a couple of days!!! Thank you thank you