Effect Measure

IIRC cytokine storm is also the mechanism implicated in Sin Nombre hantavirus fatalities.

Posted by: D. C. Sessions | May 4, 2009 8:25 PM

I haven’t seen a specific cause of death mentioned, but my guess would be that it is multiple organ failure secondary to mitochondria shut-down.

My hypothesis is that is the “generic” cause of death during extreme immune system activation, mitochondrial failure. Which organ fails first is a detail of that individual’s idiosyncratic physiology.

I talk about the mechanism in my blog of about a year ago (in a lot more detail and with links to the literature). What happens is the very high levels of NO from all the iNOS increase the ATP level via sGC. This has been demonstrated by muscle biopsy of people in sepsis. They had higher skeletal muscle ATP levels than did controls who were not in sepsis. This is good, and a generic need during an infection, it cranks up autophagy which is necessary to clear out everything that is in cells that doesn’t belong, like bacteria. High ATP is necessary to clear intracellular infections like TB and Lyme.

The high ATP comes from glycolysis, and the high ATP level mostly shuts down the mitochondria (which is good because they can’t operate in a high NO environment). To support enough glycolysis, the body needs gigantic amounts of glucose, more than can be supplied via normal liver metabolism. What the body does is turn the muscles to alanine, then turn the alanine into glucose. Once the glucose is turned into lactate, there isn’t enough mitochondrial capacity to recycle it back into glucose via the Cori cycle, so the body disposes of it by turning it into fat. During sepsis you lose muscle and gain fat. You can lose tens of pounds of muscle in a few days. That is because making ATP from glucose is so inefficient.

If there is enough glucose to support enough glycolysis, then the ATP level remains high and the mitochondria remain off. If there isn’t enough glucose, then the ATP level falls and the mitochondria turn on. This presents a problem. In the high NO environment from iNOS, cytochrome c oxidase is blocked by NO and doesn’t reduce O2 to H2O. The mitochondria need to remove this NO to unblock cytochrome c oxidase. To do that they generate superoxide. Superoxide reacts with NO at near diffusion limited kinetics. Mitochondria have unlimited capacity to produce superoxide. They produce superoxide whenever they are called on to produce power, and the respiration chain is reduced. The respiration chain only gets reduced when the electrons can’t flow off it and onto cytochrome c oxidase. When it is blocked with NO, then superoxide is produced, the superoxide pulls down the NO level, the respiration chain becomes unblocked and ATP generation can occur at a high rate.

The superoxide is generated on the inside of the mitochondria matrix where there is the mitochondrial superoxide dismutase, MnSOD. This reacts with superoxide at near diffusion limited kinetics too. There is a delicate balance between the superoxide reacting with NO and forming peroxynitrite and the superoxide being dismutated by MnSOD. Peroxynitrite can nitrate proteins, and in human MnSOD the nitration of a single tyrosine causes inhibition. In bacterial FeSOD (which is highly homologous to hMnSOD), there is no inhibition when 8 out of 9 tyrosines are nitrated. Since both enzymes are highly homologous, they evolved from a common ancestor. Since FeSOD is not inhibited by nitration, inhibition by nitration is not an inherent property of SOD. If bacteria could evolve resistance to inhibition by nitration, so could hMnSOD. It didn’t, implying that the inhibition by nitration isn’t a bug, it is a feature. I think that feature is to provide a shut-off mechanism when mitochondria start to produce too much superoxide.

Organisms can tolerate the loss of a few percent of their mitochondria; they cannot tolerate a few percent of their mitochondria making superoxide at their maximum rate.

Once too many mitochondria get shut off, the ATP level in the cells irreversibly falls and the cell dies, if too many cells die, the organ dies, if too many organs die, the organism dies. Once that happens, death is irreversible. I think that is why you feel so weak during immune system stimulation, it is to prevent you from using ATP because the threshold for irreversible damage is much lower.

The only ways I can think of to reduce this is via prevention. Prevent the very high NO levels in the first place, increase pre-exposure mitochondria number to provide more of a reserve, reduce ATP consumption as much as possible (i.e. respirators reduce the metabolic load on the lung muscles and so reduce their ATP requirements), supply glucose intravenously (to hyperglycemic levels if possible), remove lactate by dialysis with urea containing fluids, give insulin to get the glucose into the cells at high enough rates for them to use it. You really want to prevent the ATP level from falling because once it does, it is too late and you are SOL.

Posted by: daedalus2u | May 5, 2009 1:38 PM

ATP, not adenosine. ATP is adenosine tri phosphate. It is adenosine with 3 phosphates attached to it.

It is the mitochondria's "normal" function to turn off when they make too much superoxide for the NO environment they are in. All mitochondria eventually turn off. Either they turn off by making too much superoxide which nitrates things and inhibits them, or they make not enough superoxide in which case cytochrome c is released from the inter-membrane space which causes them to make more superoxide. The only way they can’t make any superoxide is when the mitochondria potential falls so much that they can’t make any ATP. Then they start consuming ATP to maintain the mitochondrial potential.

Mitochondria turning off is like a circuit breaker. There are multiple control mechanisms that do it, some are reversible, but reversing them depends on a supply of ATP. If there isn’t any, either from other mitochondria or from glycolysis, then the cell is SOL. The final turn-off is like a fuse, a one time irreversible turn off. Mitochondria have a finite lifetime, the longest lived are in the CNS. In rats they last about a month.

That irreversible turn-off is what happens if you push them too hard for too long. I think that normal vigorous aerobic exercise does that to the fraction of mitochondria that are the most marginal. They get turned off and that is what causes the fatigue of very vigorous exercise. Some get turned back on, the few percent that don’t get recycled that night when you are sleeping and replaced with fresh new mitochondria. It isn’t the exercise per se that causes increased endurance, it is the replacement of the stressed out mitochondria (plus some extra) that does. Without enough rest for mitochondria replacement, that mitochondria increase can’t happen and people end up with not enough mitochondria. I think that is the mechanism for chronic fatigue syndrome; immune system stimulation under high stress conditions. The high stress lowers the NO level, disinhibits NFkB, you get a mini cytokine storm, if you can’t get your NO level high enough to replace the mitochondria that are damaged (it is NO that triggers mitochondria biogenesis) because of the chronic stress, you end up with not enough mitochondria and perpetual low NO and the low mitochondria number becomes perpetual.

I think that is the mechanism for gulf war syndrome, vaccinations with very harsh agents (i.e. anthrax) while in a war zone (a very high stress environment). Keep the stress and immune system stimulation up for a few weeks (via multiple vaccinations) and you end up with permanently depleted mitochondria. I also call that the “low NO ratchet” because with each instance of immune system stimulation the NO level can ratchet lower (due to feedback inhibition due to the high NO from the iNOS).

Posted by: daedalus2u | May 6, 2009 9:39 PM