Complex V is down in ME - does it explain Chemical Intolerance?

Complex V

Complex V (also known as ATP synthase or F0F1ATPase) is working less efficiently in cells from ME patients (1).

The ATPase Inhibitory Factor 1 (IF1) is the physiological inhibitor of the mitochondrial ATP synthase (complex V). IF1 is a mitochondrial protein with very short half-life. It is tissue-specifically expressed and primarily controlled at posttranscriptional levels. Overexpressing of IF1 leads to inhibition of the ATP synthase and the reprograming of energy metabolism to an enhanced glycolysis. This reprogramming may protect cells from cytotoxic insults (2).

Figur 1B from reference 2 shows how IF1 binds the ATP synthase and inhibits ATP synthesis. Figur 1A: The gene ATP5IF1 encodes IF1. In mice IF1 is degraded by immediate early response gene X-1 (IEX-1). The human homolog af IEX-1 is immediate early response 3 (IER3), but IER3 do not degrade IF1 (2).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156145/figure/F1/

Chemical intolerance - is IF1 involved?

ME patients have chemical intolerance (CI), also knowns as multiple chemical sensitivity (MCS). Fx, ME patients do not tolerate smoke and exhaust fumes.

Polycyclic aromatic hydrocarbons (PAHs) are found in the environmental contaminants. It has been hypothesized  that dysregulation of the aryl hydrocarbon receptor is involved in chemical intolerance (3).

Benzo[a]pyrene (B[a]P) is a prototype molecule of polycyclic aromatic hydrocarbons. B[a]P induce IF1 expression and metabolic reprogramming towards glycolysis in rat liver cells. The process may also involve β2-adrenergic receptor and aryl hydrocarbon receptor activation (4).






Figure 6 from reference 4: A proposed model for the B[a]P-mediated metabolic reprogramming and its role in cell fate determination in F258 rat hepatic epithelial cells.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428028/figure/Fig6/

Can PAH-induced IF1 upregulation put further strain on a compromised complex V in ME patient cells?

Can auto-antibodies against adrenergic receptors upregulate IF1 activity in ME patient cells?

Mutant mice with an active IF1 are partially protected from cytotoxic insults - such as quinolinic acid (2). Interestingly quinolinic acid is a kynurenine metabolite which may be dysregulated in ME patients according to the IDO metabolic trap hypothesis (5).

References

1) Missailidis, D.; Annesley, S.J.; Allan, C.Y.; Sanislav, O.; Lidbury, B.A.; Lewis, D.P.; Fisher, P.R. An isolated Complex V defect and dysregulated mitochondrial function in immortalized lymphocytes from ME/CFS patients. Submitted 2019.

Specific Mitochondrial Respiratory Defects & Compensatory Changes in ME/CFS Patient Cells

https://www.youtube.com/watch?v=SjK39QCPeeY

2) García-Aguilar A and Cuezva JM (2018).  A Review of the Inhibition of the Mitochondrial ATP Synthase by IF1 in vivo: Reprogramming Energy Metabolism and Inducing Mitohormesis. Front. Physiol. 9:1322. doi: 10.3389/fphys.2018.01322

https://www.frontiersin.org/articles/10.3389/fphys.2018.01322/full

3) de Luca et al: Biological definition of multiple chemical sensitivity from redox state and cytokine profiling and not from polymorphisms of xenobiotic-metabolizing enzymes. Toxicol Appl Pharmacol. 2010 Nov 1;248(3):285-92. doi: 10.1016/j.taap.2010.04.017. Epub 2010 Apr 27. https://www.ncbi.nlm.nih.gov/pubmed/20430047

4) Kévin Hardonnière, Morgane Fernier, Isabelle Gallais, Baharia Mograbi, Normand Podechard, Eric Le Ferrec, Nathalie Grova, Brice Appenzeller, Agnès Burel, Martine Chevanne,, Odile Sergent, Laurence Huc, Sylvie Bortoli & Dominique LagadicGossmann (2017): Role for the ATPase inhibitory factor 1 in the environmental carcinogen-induced Warburg phenotype. Nature scientific reports | 7: 195 | DOI:10.1038/s41598-017-00269-7

https://www.nature.com/articles/s41598-017-00269-7

5) Metabolic Traps in ME/CFS - Research Update by Dr. Robert Phair https://www.youtube.com/watch?v=Quh-77gvw4Q

IDO-ME hypotesen er forenelig med AHR-MCS hypotesen (in danish - use the english references in the blog post)

http://followmeindenmark.blogspot.com/2019/06/ido-me-hypotesen-er-forenelig-med-ahr.html

Kynurenine metabolisme påvirkes af motion (in danish - use the english references in the blog post)

http://followmeindenmark.blogspot.com/2019/06/kynurenine-metabolisme-pavirkes-af.html

Tryptofan metabolitten kynureninsyre har immunmodulerende egenskaber (in danish - use the english references in the blog post)

http://followmeindenmark.blogspot.com/2019/06/tryptofan-metabolitten-kynureninsyre.html

Is the kynurenic acid responsive Gpr35 involved in the ME pathomechanism?

http://followmeindenmark.blogspot.com/2019/06/is-kynurenic-acid-responsive-gpr35.html