Thursday, March 14, 2013

Protons: Back to N-1a and a nice quote

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.

2 comments:

Ian said...

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

Jack Kruse said...

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.