Mitochondria have their own separate fatty acid synthesis mechanism

[anciendaze]

This post on Phys.org just caught my eye. I didn't realize there was a distinct mitochondrial cycle for this essential part of cell metabolism. Here's the primary citation.

This is the first I have heard of MEPAN and the foundation to study it. This devastating disease could be a key to the kind of breakdown most of us experience only partially.

 

[alex3619]

Biology and medicine are still in their infancy so far as I see. There is so much more to learn. I love reading things like this.

 

[spinoza577]

Here is another article on this theme:

Evidence for Physical Association of Mitochondrial Fatty Acid Oxidation and Oxidative Phosphorylation Complexes Wang et a 2010

from the intro, referring what was known (my pragraphs)

Mitochondria are the site of three of the most important energy generating pathways in humans: oxidative phosphorylation (OXPHOS),2 fatty acid β-oxidation (FAO), and the tricarboxylic acid cycle. OXPHOS is carried out by >150 structural and enzymatic proteins embedded within the inner mitochondrial membrane organized into five functional electron transport chain (ETC) complexes I–V.

Blue native gel electrophoresis (BNGE) shows that the ETC complexes associate into higher order structures consisting of complexes I, III, and IV in varying stoichiometries termed supercomplexes. Two supercomplexes species have been identified in Saccharomyces cerevisiae consisting of dimeric complex III with one or two copies of monomeric complex IV (III2+IV1–2) (1, 2). In mammalian and plant studies, a supercomplex containing a dimeric complex III has been shown to associate through the inner mitochondrial membrane to an arm of complex I (I1+III2) (3, 4). Additionally, a supercomplex consisting of one complex I, dimeric complex III, and one to four copies of complex IV (I1+III2+IV1–4) was identified in rat muscle (5) and bovine heart mitochondria (3, 6).
...
Association into higher order supercomplexes likely mediates substrate channeling leading to enhanced stability, higher electron transfer rates, greater catalytic efficiency, and sequestration of reactive intermediates (6).

And then their finding is, of course and as in the title indicated, that FAO seems to be a part of such regular supercomplexes.

 

[DMissa]

Fatty acid metabolism is something that's becoming more discussed in the ME/CFS field lately. This arm of it (mito FA biosynthesis) is something which has definitely been thought about but I don't really think discussed at length yet in the literature. I did already look at the small handful of involved enzymes in my -omics results but couldn't see evidence of much different, expression wise.

Can't read full article linked in the OP since paywalled and my university VPN isn't working today, but found a summary elsewhere. Interesting to think about is that knockout of 3 genes in this pathway (the ones which are not also complex subunits) seemed to impair oxphos complex assembly and subunit expression, particularly Complex 1 and Complex 2. The specific subunits most highlighted here (NDUAB and SdhB) have instead been observed pretty consistently to be elevated in expression in ME/CFS (and their complexes functioning normally in their relative individual contributions to electron transport).

There is so much more to learn.

Most definitely. But even in our own field here, I have seen so much progress and new groups popping up since I entered that it is heartening.

 

[alex3619]

Fatty acid metabolism is something that's becoming more discussed in the ME/CFS field lately.

This was where I started into it all. FA metabolism was my special topic back in the 90s through 2000s. Sadly my cognitive decline has left me more and more out of date, and I have forgotten most of it, but even back then I thought it likely to be important. I was also into glutathione theory and hypoxia theory. Now we are seeing a merging of different research lines, and multiple lines of research, from different directions, reaching the same conclusions. I take that as a promising sign.

Let me briefly discuss one issue I have harped on over the years. The presence of a chemical does not mean its functioning. Glutathione is needed for proper protein folding, and I pointed out that the presence of sufficient aconitase (for example) does not mean its working. Now we suspect that complexes are not forming right. So they might be present, but if they are not structurally assembled the right way the presence of the mere chemicals may not be enough.

 

[anciendaze]

I'm still not able to keep up with all this, because I can only sit and type for limited time before my back complains.

What I realized at the outset is that this could explain why various tests of mitochondrial function could fail to find abnormalities in ME/CFS.

Here's an overview of the role of mitochondrial genetics. What many people have long known is that quite a number of mitochondrial genes have migrated to the cell nucleus where they are better protected from transcription errors. This means mitochondria can no longer live as independent organisms. Moreover, the division of genes between mitochondria and nucleus is different in different species. You can't even expect to move mitochondria to other species. This contributes to the reproductive isolation that defines true species.

What had escaped me was that mitochondria have retained a complete system of fatty acid synthesis for their own purposes, not simply a grab bag of relevant genes, even though cells have a robust system of their own. This means you can't simply test for various molecules in these cycles, unless you can distinguish those in the mitochondrial FAS cycle from those in the cell's FAS cycle. The cell may have an undamaged cycle, but still have problems with mitochondria.

I've also noted that mtDNA is more vulnerable to viral infection than nuclear DNA. This fits in with an old observation that prolonged unexplained fatigue is more likely to follow viral infections.

Added Afterthought: possible complications.
Viral infections tend to target particular cell types. Most cells could be unaffected, but some, like nerve cells, could function way below par. Worse, the problem might not be a simple as reduced numbers of mitochondria. It could be a shift in populations to less effective mitochondria. Do we have to consider a change in mitochondrial heteroplasmy which only applies to specific cell types?

Can someone come up with a way around these problems? Convincing doctors of such things could be really difficult.

 

[anciendaze]

I'm not committed to the hypothesis that direct viral infection causes our troubles. The variety of possible triggers points to some kind of misdirected immune response, though viruses, and RNA viruses in particular are high on the list of suspects. Humans are just now developing RNA vaccines. As always we think we are pretty clever. I'm wondering if nature got there ahead of us. Viral infections do dump a good bit of mRNA into the bloodstream, and this could trigger immune responses separate from those depending on traditional pathways.