@Valentijn , do you think that the NDUFAF1 gene is relevant in this thread?
http://www.genecards.org/cgi-bin/carddisp.pl?gene=NDUFAF1
https://www.omim.org/entry/252010
I suppose that you already know that Metformin is an inhibitor of Mitochondrial complexe I (see below)
Next time you purchase CoQ10 keep the following points in mind:
• Both CoQ10 forms—ubiquinone and ubiquinol—are important, effective and do great things for your body
•
The body is extremely intelligent and is capable of turning one form of CoQ10 into the other as needed
• Feel great that you are choosing such a important supplement for your health
http://www.naturemade.com/resource-...h/understanding-coq10-ubiquinone-vs-ubiquinol
it could be that my body isn't that clever...
I stopped Ubiquinol (I tryed several dosage from 50 mg to 200 mg:day) for a week because of the side effects, and switched to Ubiquinone (360 mg/day)....during this week I gradually went back to the "broken doll" state, with big difficulties walking and marked muscles weakness, and increased lumbar pain.
I took again 50 mg Ubiquinol and felt my muscle strength back...
But if I stop Ubiquinone, my lactates levels go higher....
It seems that my
mitochondrial complexe I , the NADH ubiquinone reductase, an important enzyme which allows this reaction:
NADH + H+ + ubiquinone
NAD+ + ubiquinol
is not working like it should ...and that I need to take both supplements!
I checked my missense mutations with some protein impact for this complexe I (gene NDUFAF1) and I have two heterozygous common ones
rs3204853 CA
rs1899 CT
allele frequency for these mutations are about 20% which is high, and they are labeled as "likely benign"...
(I have also a very common homozygous nonsense mutation on NDUFB9 rs6470252 TT of unknown significance)
so what!
is it that
-I don't take enough NADH supplement to convert Ubiquinone to Ubiquinol?
-something inhibits my complexe I enzyme?
I found a review of complexe I inhibitors (1998) here
http://www.sciencedirect.com/science/article/pii/S0005272898000292
But it may need an update!
A more recent publication is about complexe I inhibition by Palmitate
http://www.biochemj.org/content/ppbiochemj/387/3/677.full.pdf
Do I have too much palmitate in blood? Something that I need to dig in!
Good night folks, it's late here....
Edit: Looking at wikipedia page for this enzyme, the section about inhibitors is much informative!
"Bullatacin (an
acetogenin found in
Asimina triloba fruit) is the most potent known inhibitor of NADH dehydrogenase (ubiquinone) (IC50=1.2 nM, stronger than rotenone).
[37] The best-known inhibitor of complex I is
rotenone (commonly used as an organic pesticide). Rotenone and rotenoids are
isoflavonoids occurring in several genera of tropical plants such as Antonia (
Loganiaceae),
Derris and
Lonchocarpus (
Faboideae,
Fabaceae). There have been reports of the indigenous people of French Guiana using rotenone-containing plants to fish - due to its ichthyotoxic effect - as early as the 17th century.
[38] Rotenone binds to the
ubiquinone binding site of complex I as well as
piericidin A, another potent inhibitor with a close structural homologue to ubiquinone.
Acetogenins from
Annonaceae are even more potent inhibitors of complex I. They cross-link to the ND2 subunit, which suggests that ND2 is essential for quinone-binding.
[3] Interestingly, Rolliniastatin-2, an acetogenin, is the first complex I inhibitor found that does not share the same binding site as rotenone.
[39]
Despite more than 50 years of study of complex I, no inhibitors blocking the electron flow inside the enzyme have been found. Hydrophobic inhibitors like rotenone or piericidin most likely disrupt the electron transfer between the terminal FeS cluster N2 and ubiquinone. It has been shown that long-term systemic inhibition of complex I by rotenone can induce selective degeneration of dopaminergic neurons.
[40]
Complex I is also blocked by adenosine diphosphate ribose – a reversible competitive inhibitor of NADH oxidation – by binding to the enzyme at the nucleotide binding site.[41] Both hydrophilic NADH and hydrophobic ubiquinone analogs act at the beginning and the end of the internal electron-transport pathway, respectively.
The antidiabetic drug Metformin has been shown to induce a mild and transient inhibition of the mitochondrial respiratory chain complex I, and this inhibition appears to play a key role in its mechanism of action.
[42]
Inhibition of complex I has been implicated in
hepatotoxicity associated with a variety of drugs, for instance
flutamide and
nefazodone.
[43]"
