My name is Martin Brand from the Buck Institute for Research on Aging in Novato.
And I want to talk to you today about
Mitochondrial Production of Reactive Oxygen Species.
The next slide introduces that.
So what I'm going to tell you is that there are
many different sites within mitochondria which are
able to generate superoxide or hydrogen peroxide,
the reactive oxygen species I'm going to be talking about.
Their contributions change depending on the substrates and the conditions.
And under near-physiological conditions,
we think that at least in skeletal muscle, four sites dominate.
So, I'll talk about those four sites.
And then once we've characterized the sites and understood something of their properties,
I'll talk about our endeavors to suppress them, small molecule suppressors.
I'll introduce suppressors of electron leaked cells which can
prevent particular sites from running without affecting oxidative phosphorylation.
And then talk about how those tools allow us to
understand how the sites are operating in physiology and pathology.
So the next slide introduces the production of radicals.
Reactive oxygen species are generated when oxygen is reduced by electrons.
The normal reaction is that four electrons reduce an oxygen molecule to give water,
and that's a harmless reaction,
and the intermediates are kept very closely under control by the biological system.
However, if the electrons pass on to oxygen either singly or in pairs,
then you get formation of superoxide or of hydrogen peroxide.
So, a single electron going onto oxygen will give us a superoxide radical,
and a pair of electrons going into oxygen will give us a hydrogen peroxide.
And superoxide and hydrogen peroxide are
reactive oxygen species that can interact with proteins,
with DNA, with lipids,
and can cause both Redox Signaling effects,
and pathologies, and damage.
And the next slide addresses the question of how do we know what the rates of
these undesirable or signalling pathways are in a biological context.
And a common misconception is that
a certain proportion of the electron flow may be diverted into radical production.
So you'll see in the literature that two percent or half a percent
of the oxygen consumed by mitochondria can be used to make free radicals,
and that's not a useful way to think about.
Biology has no way of discerning flows,
no way of dividing flows between different branches.
Instead what happens is that the concentration of intermediates,
in this case X minus,
determines the production rates of superoxide.
So we can ask ourselves what is it that