Cardiolipin-induced activation of pyruvate dehydrogenase links mitochondrial lipid biosynthesis to TCA cycle function, 2019, Greenburg et al

Andy · Jun 13, 2019

In mice!

Abstract
Cardiolipin[MS1] (CL) is the signature phospholipid of mitochondrial membranes. Although it has long been known that CL plays an important role in mitochondrial bioenergetics, recent evidence in the yeast model indicates that CL is also essential for intermediary metabolism.

To gain insight into the function of CL in energy metabolism in mammalian cells, here we analyzed the metabolic flux of [U-13C]glucose in a mouse C2C12 myoblast cell line, TAZ-KO, which is CL-deficient because of a CRISPR/Cas9-mediated knockout of the CL-remodeling enzyme tafazzin (TAZ). TAZ-KO cells exhibited decreased flux of [U-13C]glucose to [13C]acetyl-CoA and M2 and M4 isotopomers of TCA cycle intermediates. Activity of pyruvate carboxylase (PC), the predominant enzyme for anaplerotic replenishing of the TCA cycle, was elevated in the TAZ-KO cells, which also exhibited increased sensitivity to the PC inhibitor phenylacetate.

We attributed a decreased carbon flux from glucose to acetyl-CoA in the TAZ-KO cells to a ~50% decrease in pyruvate dehydrogenase (PDH) activity, which was observed in both TAZ-KO cells and cardiac tissue from TAZ-KO mice. Protein–lipid overlay experiments revealed that PDH binds to CL, and supplementing digitonin-solubilized TAZ-KO mitochondria with CL restored PDH activity to wildtype levels. Mitochondria from TAZ-KO cells exhibited an increase in phosphorylated PDH, levels of which were reduced in the presence of supplemented CL. These findings indicate that CL is required for optimal PDH activation, generation of acetyl-CoA, and TCA cycle function, findings that link the key mitochondrial lipid CL to TCA cycle function and energy metabolism.
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Open access at http://www.jbc.org/content/early/2019/06/11/jbc.RA119.009037

sb4 · Jun 14, 2019

Very interesting. Ties the PDH stuff to the high levels of Cardiolipin antibodies.

Mithriel · Jun 14, 2019

All the cardiolipin research into ME seems to have disappeared since the death of the Hawaiian doctor who did most of the work. I remember people complaining that the NIH was also doing work on it but used different terminology so it was all becoming confused then nothing more was said. It had seemed promising.

Jaybee00 · Jun 17, 2019

@Andy Thanks for finding/posting this article....

CL=cardiolipin

In this study, we show for the first time that
CL is required for optimal activity of the acetylCoA biosynthetic enzyme PDH and TCA cycle
function. CL-deficient TAZ-KO cells exhibited
decreased PDH activity (Fig. 6), increased levels
of the phosphorylated, inactive enzyme (Fig.
8A), and decreased flux of glucose to acetylCoA and TCA cycle intermediates (Figs. 1-2)... These
findings identify a regulatory link between the
mitochondrial membrane lipid CL and the
reactions of energy metabolism in the
mitochondrial matrix.
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Now if only we had a compound that could bind to cardiolipin and increase and improve mitochondrial respiration and function......

Slamdancin · Jun 18, 2019

Jaybee00 said: ↑

@Andy Thanks for finding/posting this article....

CL=cardiolipin

Now if only we had a compound that could bind to cardiolipin and increase and improve mitochondrial respiration and function......
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Are you hinting at a compound you know of? I’d be quite interested in taking a look at such a thing.

S-VV · Jun 18, 2019

SS-31 protects and restores cardiolipin

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976620/

Trish · Jun 18, 2019

S-VV said: ↑

SS-31 protects and restores cardiolipin

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976620/
Click to expand...

That paper is from 2014 and only talks about animal studies. Is there anything more up to date or any human trials?

S-VV · Jun 18, 2019

SS-31 is still early in the pipeline, so not many human studies. Here is a phase II one for renal artery stentosis.

https://www.ahajournals.org/doi/10.1161/CIRCINTERVENTIONS.117.005487

Wonko · Jun 19, 2019

Andy said: ↑

In mice!
Click to expand...

Not whole mice, tiny little bits of mice, at least according to a rather confused and cursory reading of the abstract you posted.

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Cardiolipin-induced activation of pyruvate dehydrogenase links mitochondrial lipid biosynthesis to TCA cycle function, 2019, Greenburg et al

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Cardiolipin-induced activation of pyruvate dehydrogenase links mitochondrial lipid biosynthesis to TCA cycle function, 2019, Greenburg et al

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