Eureka moment when I tripped over this gem by Vinogradov
"The redox potential of one binuclear [FeS] center (N-1a) is so negative that it can not be reduced by NADH"
Couple this with this group's conclusion:
"These
results lead us to propose a model of thermodynamic control of
mitochondrial ROS production which suggests that the ROS-generating site
of complex I is the Fe-S centre N-1a".
You can't
reduce N-1a to generate superoxide using NADH at "normal"
concnetrations. The easiest way you can generate superoxide at N-1a is
by reverse electron flow through complex 1 under conditions of a strong
membrane potential and a high FADH2 input, in this case using succinate.
Very satisfying. They also point out that, if you can get the NAD+/NADH
ratio high enough you can get it far enough from its electrical mid
point to pass electrons "down gradient" to N-1a. At ratios of less than
about 3 parts NADH to one part NAD+ the transfer is uphill and isn't
going to happen. As they say:
"...the reduction of the *ROS site [they consider that it is probably N-1a] is regulated by the NADH/NAD+ ratio rather than the NADH level (eqns 7 and 8)..."
which
sort of takes us back to B3 and some cancer cells which have probably
lost N-1a so fail to develop insulin resistance, ie they don't limit
their energy generation to their needs. They also develop metastatic
aggressiveness in proportion to their elevated NADH:NAD+ ratio (even if
they expressed it as a reduced NAD+/NADH ratio!). I wrote that post a
while ago, time to check it and hit publish...
Peter
BTW
Vinogradov pointed out in his review paper that very few labs have the
massively expensive and complex gear to look at this sort of redox
research and both of the papers discussed here are from groups who know
each other, Vinogradov being thanked for reading through the manuscript
of the second paper. But I think they are correct.
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2 comments:
This is amazing! I'm currently taking a bhiochemistry class and it's fantastic to see these sorts of conclusions while being able to understand what you're saying
Pete you got to look into the transition metal angle and the electromagentic force. They key is the delocalized D shell electrons. It makes them controllable to the force. This is how bad cellular signaling is found in mitochondria controlling this switch. These metals are how supernova's happen. They are used in all types of evolutionary switches because the sub atomic particle that reacts best with the electromagnetic force is the negatively charged electron. Out of the 4 physical forces the electromagnetic is the strongest because it has strong local effects but infinite range. The infinite range is how biology controls the D shell electrons on mitochondria. This is why people do not understand the effect of ketones on a lowed transmembrane potential. They have no idea how the Hall effect works to reverse flow. You are closer to anyone in biology or the blogosphere in getting this.......but you got to look into the QED of electron flow to complete the loop of wisdom.
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