Comment on "Protons (60) 4-hydroxy-2-nonenal [HNE]"

A key post, and I think my comment is important enough to reproduce here.

---

Nice post. I have nothing to add to my comment on your previous discussion of Speijer's "Q" paper (replying to @Kenneth Strain), where I noted Speijer's observation:

"Here, palmitate (saturated C-16) and an oxidized (!) FA (4-hydroxy-2-nonenal) enhanced UCP proton transport."

I commented:

"4-hydroxy-2-nonenal is 4-HNE, and so the breakdown of TLCL is a fundamental part of mitochrondial function and regulation.

"The problem occurs, based on my reading, when TLCL overwhelms the regulatory/reactive systems. One sees this is occurring when glutathione (GSH) is diminished, and HNE is escaping the mitochondria unbound to GSH to wreak havoc on surrounding structures, like DNA. The presence of HNE bound to various other things is a marker for every part of the MetS, broadly defined, which includes cardiovascular disease and Alzheimer's. It's everywhere, along with the other N-6 peroxides."

I don't have anything to add to that, as I think it's spot on, even after three years of learning.

It's why my post (in response to Peter and Dr. Eades's discussions) explaining the fundamental problem in these processes contains the word "EXCESS":

"The Cause of Metabolic Syndrome: Excess Omega-6 Fats (Linoleic Acid) in Your Mitochondria"

Peter observes above:

"So UCPs in general appear to respond to an inappropriately high level of ROS generation by activating the safety valve of uncoupling the mitochondrial membrane potential. Linoleic acid derived 4-HNE is key to this process."

And yes, you can certainly figure out ways to tweak the inputs to alter the outputs. But these are generally non-physiological tweaks, and are not without their own hazards. So you can use "F3666 high PUFA ketogenic rodent food", but you will still kill the liver, as I noted in this post:

"Hello, Can We Have Your Liver?"": Understanding a High-PUFA Diet.

Where a high PUFA diet produces a better outcome, in some respects: 

"tl;dr: A diet high in omega-6 and omega-3 polyunsaturated fatty acids has some positive effects on the body: lower weight gain, better preservation of lean mass..."

But, as with Maratos-Flier's keto mouse experiments, it still kills the liver via steatosis, even when weight gain is not part of the outcome.

As Peter also notes, excess n-6 is not something you want. HNE does loads of other fun things, too, as it damages ~24% of the proteins in the cell. Just check out what it does to ATP!

Omega-6 HNE breaks ATP synthase, hence mitochondria, early in Alzheimer’s. @puddleg https://t.co/lCjmoD1crc

— Tucker Goodrich (@TuckerGoodrich) October 2, 2017