En ny biosensor viser, at SS-31 er et potentielt lægemiddel til ME

Dr. Ron Davis fra Standford Universitet og hans team har udviklet en nano-elektrisk biosensor (på engelsk populært kaldet "the nanoneedle"). Den kan vise om immunceller fra en blodprøve kommer fra ME patienter eller fra raske kontrolpersoner.

Immunceller fra både ME patienter og raske kontrolpersoner udsættes for salt-stress (også kaldet osmotisk stress) i biosensoren ved, at der tilsættes en natriumklorid-opløsning. Biosensoren måler et elektrisk signal (impedansen), som er et resultat af celleprocesser udløst af salt-stress.

Forskningen er beskrevet i denne artikel:
A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
https://www.pnas.org/content/116/21/10250.long

Dr. Ron Davis forsøger nu at finde et lægemiddel, der kan normalisere ME-cellers respons på salt-stress. Han afprøver forskellige lægemidler ved at tilsætte dem til blod fra ME patienter i biosensoren.

To lægemidler får celler fra ME blodprøver til at opføre sig normalt i biosensoren. Disse resultater blev fremlagt på Havard Symposium 2019:

Dr. Ron Davis Presents on ME/CFS Research Activities at Stanford at Inaugural Harvard Symposium

https://www.youtube.com/watch?v=02TUcGqTFAI&t=37s

Det ene lægemiddel er:  

Copaxone med indholdsstoffet hedder Glatirameracetate. Læs om det her: http://pro.medicin.dk/Medicin/Praeparater/2889

Det andet lægemiddel, som jeg synes er mest interessant, er:

SS-31, Szeto-Schiller Peptide 31, Elamipretide. Lægemidlet er endnu ikke godkendt, men der arbejdes med det på forsøgsbasis. Læs om det her: 

Mitochondrial dysfunction and oxidative stress in metabolic disorders - A step towards mitochondria based therapeutic strategies
https://www.ncbi.nlm.nih.gov/pubmed/27836629

The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes
https://www.ncbi.nlm.nih.gov/pubmed/31466264

Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice
https://www.ncbi.nlm.nih.gov/pubmed/30597195

The mitochondrial antioxidant SS-31 increases SIRT1 levels and ameliorates inflammation, oxidative stress and leukocyte-endothelium interactions in type 2 diabetes
https://www.ncbi.nlm.nih.gov/pubmed/30367115

SS-31 Provides Neuroprotection by Reversing Mitochondrial Dysfunction after Traumatic Brain Injury
https://www.ncbi.nlm.nih.gov/pubmed/30224944

From the muscle hypothesis to a muscle solution?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437437/

Novel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide
https://www.ncbi.nlm.nih.gov/pubmed/29217757

Therapies for mitochondrial diseases and current clinical trials
https://www.ncbi.nlm.nih.gov/pubmed/28943110

OMICS and iron metabolism in ME

Genomics in ME

Gene variants of TF, TFRC, and HPX have been identified as risk loci in ME patients (1):




Slide from: Whole Genome Sequencing and Analysis of ME/CFS
https://www.youtube.com/watch?v=nIJX-Q7w_Z4


Serotransferrin (usually just called transferrin), TF: iron-binding protein

Transferrin receptor, TFRC: plasma membrane protein that allows cellular uptake of iron-loaded transferrin

Hemopexin, HPX: a protein that binds free heme (or met-heme) and transport it to the liver for break-down and iron recovery.

Haptoglobin, HP: a protein that binds free hemoglobin and transport it to the liver for break-down and iron recovery.

Hemopexin and haptoglobin prevent heme toxicity.

Proteomics in ME

Serotransferrin precursor (gene: TF), number of unique peptides identified in the cerebrospinal fluid (table S1 in ref 2):

1) Controls: 105

2) ME patients: 141

3) Post treatment Lyme patients: 105

Transferrin variant fragment  (gene: TF), number of unique peptides identified in the cerebrospinal fluid (table S1 in ref 2):

1) Controls: 104

2) ME patients: 130

3) Post treatment Lyme patients: 99

Transferrin receptor protein 1 (gene: TFRC), number of unique peptides identified in the cerebrospinal fluid (table S1 in ref 2):

1) Controls: 1

2) ME patients: 2

3) Post treatment Lyme patients: 3

Haptoglobin precursor (gene: HP) , number of unique peptides identified in the cerebrospinal fluid (table S1 in ref 2).

1) Controls: 30

2) ME patients: 39

3) Post treatment Lyme patients: 34

Hemopexin precursor (gene: HPX) , number of unique peptides identified in the cerebrospinal fluid (table S1 in ref 2).

1) Controls: 61

2) ME patients: 197

3) Post treatment Lyme patients: 189

Another proteome study on cerebrospinal fluid from ME patients also showed increased levels of hemopexin and haptoglobin (3).

Metabolomics in ME

A metabolomic study on plasma from ME patients showed increased levels of heme (4).

Methemoglobin in ME

A study showed increased levels of methemoglobin in ME patients. Methemoglobin was found to be the major component associated with variation in symptom expression in ME patients (R(2) = 0.99, P <0.00001), which included fatigue, musculoskeletal symptoms, pain and sleep disturbance (5).

Activated macrophages produce an inducible NO synthase (iNOS or NOS2). This NO produced during inflammation and other oxygen reactive species results in conversion of hemoglobin to methemoglobin, and this consequently results in an increased rigidity of the red blood cell (RBC) with increased RBC lysis (6).  

Methemoglobin is an activator of endothelial cells by stimulation of IL-6, IL-8 and E-selectin (6).

Red blood cell deformability is diminished in ME patients (7).

Genomics, proteomics and transcriptomics show the iNOS pathway is upregulated in ME (8).

References:

1) Whole Genome Sequencing and Analysis of ME/CFS https://www.youtube.com/watch?v=nIJX-Q7w_Z4

2) Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issuehttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287

3) Baraniuk et al: A Chronic Fatigue Syndrome - related proteome in human cerebrospinal fluid. BMC Neurol. 2005 Dec 1;5:22. https://www.ncbi.nlm.nih.gov/pubmed/16321154

4) Germain et al: Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. 2018 Dec 6;8(4). pii: E90. doi: 10.3390/metabo8040090.
https://www.ncbi.nlm.nih.gov/pubmed/30563204

5) Richards et al: Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome. Redox Rep. 2000;5(1):35-41. https://www.ncbi.nlm.nih.gov/pubmed/10905542

6) Umbreit: Methemoglobin--it's not just blue: a concise review. Am J Hematol. 2007 Feb;82(2):134-44. https://www.ncbi.nlm.nih.gov/pubmed/16986127

7) Saha et al: Red blood cell deformability is diminished in patients with Chronic Fatigue Syndrome. Clin Hemorheol Microcirc. 2019;71(1):113-116. doi: 10.3233/CH-180469. https://www.ncbi.nlm.nih.gov/pubmed/30594919

8) Genomics, proteomics and transcriptomics show the iNOS pathway is upregulated in ME. https://followmeindenmark.blogspot.com/2019/09/genomics-proteomics-and-transcriptomics.html

Genomics and the cytokine network in ME

Genomics in ME

Gene variants of IL12B, IL1B and IL4R have been identified as a risk loci in ME (1):

Slide from: Whole Genome Sequencing and Analysis of ME/CFS
https://www.youtube.com/watch?v=nIJX-Q7w_Z4

Cytokines in ME

Plasma cytokine levels have been measured in ME patients with short-duration illness (≤3 years) and ME patients with long-duration illness (>3 years) (2).

IL-12B (IL-12p40) was increased in short-duration and decreased in long-duration compared to normal controls.

IL-1β was decreased in long-duration compared to short-duration and normal controls (2).

IL4 was increased in short-duration and decreased in long-duration compared to normal controls (2).

Interferon-γ (IFNγ) was decreased in long-duration compared to short-duration and normal controls (2).

Cytokines and IDO1

IL-12B stimulate the production of IFNγ, and  IFNγ induce IDO1 activity (3).

IDO1 is inhibited by IL-4 (3).

Do the risk loci play a role in the ME-IDO-metabolic trap hypothesis?

Further reading:

Genomics, proteomics and transcriptomics show the iNOS pathway is upregulated in ME
http://followmeindenmark.blogspot.com/2019/09/genomics-proteomics-and-transcriptomics.html

References:

1) Whole Genome Sequencing and Analysis of ME/CFS https://www.youtube.com/watch?v=nIJX-Q7w_Z4

2) Hornig et al: Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv. 2015 Feb;1(1). pii: e1400121.  https://www.ncbi.nlm.nih.gov/pubmed/26079000

3) Opitz et al: Tryptophan degradation in autoimmune diseases. Cell Mol Life Sci. 2007 Oct;64(19-20):2542-63. https://www.ncbi.nlm.nih.gov/pubmed/17611712

Genomics, proteomics and transcriptomics show the iNOS pathway is upregulated in ME

Activated macrophages produce an inducible NO synthase (iNOS or NOS2).  Although iNOS was originally identified and characterized in macrophages, it is present in numerous cell types including endothelial cells, fibroblasts, vascular smooth muscle cells and cardiac myocytes (1).

Genomics in ME

A gene variant of iNOS has been identified as a risk locus in ME (2):

Slide from. Whole Genome Sequencing and Analysis of ME/CFS

https://www.youtube.com/watch?v=nIJX-Q7w_Z4 

Proteomics in ME

The pathway "Production of NO and ROS in macrophages" was upregulated in the cerebrospinal fluid from ME patients (table S6 in ref 3).

Transcriptomics in ME

Functional Network Analysys of gene transcripts from ME immune cells showed thar the pathway "Production of NO and ROS in macrophages" was enriched (p-value = 0,000018) (4).

Macrophages and the ME-IDO-metabolic trap

The ME-IDO metabolic trap hypothesis tell us that the kynurenic pathway may be blocked in dendritic cells and macrophages. This means decreased metabolites from the pathway (5).

During inflammation and resolution of inflammation, this may be going on in normal cells (6) :

• Increased IDO activity
• Increased kynurenic acid (KYNA) production
• Increased GPR35 activation (KYNA activates GPR35)
• Decreased iNOS expression

Figure 2 from ref 6 Wirthgen et al (2018).


Is this what is going on in ME macrophages???:

• Decreased IDO activity
• Decreased KYNA production
• Decreased GPR35 activation
• Increased iNOS expression

References:

1) iNOS signaling: https://www.qiagen.com/us/shop/genes-and-pathways/pathway-details/?pwid=252

2) Whole Genome Sequencing and Analysis of ME/CFS https://www.youtube.com/watch?v=nIJX-Q7w_Z4

3) Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issuehttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287

4) Sweetman et al: Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Sweetman et al: Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738418820402. doi: 10.1177/2058738418820402.
https://www.ncbi.nlm.nih.gov/pubmed/30791746

5) Kashi AA Davis RW and, Phair RD: The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS. Diagnostics (Basel). 2019 Jul 26;9(3). pii: E82. doi: 10.3390/diagnostics9030082. https://www.mdpi.com/2075-4418/9/3/82

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

6) Wirthgen E Hoeflich A, Rebl A, Günther J.: Kynurenic Acid: The Janus-Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions
Front Immunol. 2018 Jan 10;8:1957. doi: 10.3389/fimmu.2017.01957. eCollection 2017.
https://www.frontiersin.org/articles/10.3389/fimmu.2017.01957/full

Does OXA1L, MRM2 and MRRF protein activity compensate for complex V inefficiency in ME patient cells?

ATP synthesis by Complex V is less efficient in ME/CFS cells. The other mitochondrial complexes work harder to compensate (1).

Is this problem reflected in previous ME research?

OXA1L

Oxidase (cytochrome c) assembly 1-like (OXA1L) is a mitochondrial inner membrane protein. It is required for the insertion of integral membrane proteins into the mitochondrial inner membrane. Essential for the activity and assembly of cytochrome oxidase. Required for the correct biogenesis of complex V and complex I in mitochondria (2).

Knockdown of human Oxa1L impairs the biogenesis of complex V and NADH:ubiquinone oxidoreductase (3).

The C-terminal approximately 100-amino acid tail of Oxa1L (Oxa1L-CTT) binds to mitochondrial ribosomes and plays a role in the co-translational insertion of mitochondria-synthesized proteins into the inner membrane (4).

The gene OXA1L had changed DNA methylation profile and increased foldchange (2,01) in CD4+ T-cells from ME patients (5).

MRM2/FTSJ2

Mitochondrial rRNA methyltransferase 2 (also known as FTSJ2) is involved in mitoribosome assembly (6).

Defective MRM2 causes MELAS-like clinical syndrome (MELAS = mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (7).

The gene MRM2 had changed DNA methylation profile and increased foldchange (2,12) in CD4+ T cells from ME patients (5).

The gene MRM2 was hypomethylated (3'UTR) in peripheral mononuclear cells (PBMC) from ME patients (8).

MRRF

Mitochondrial ribosome-recycling factor (MRRF) is responsible for the release of ribosomes from messenger RNA at the termination of protein biosynthesis. May increase the efficiency of translation by recycling ribosomes from one round of translation to another (2).

MRRF is essentiel for cell viability and depletion of MRRF leads to loss of mitochondrial complexes (9).

MRRF gene expresseion was increased in PBMC from ME patients (10, 11). 

Does OXA1L, MRM2 and MRRF protein activity compensate for complex V inefficiency in ME patient cells?

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) Genecards: https://www.genecards.org/

3) Stiburek et al. Knockdown of human Oxa1l impairs the biogenesis of F1Fo-ATP synthase and NADH:ubiquinone oxidoreductase. J Mol Biol. 2007 Nov 23;374(2):506-16. Epub 2007 Sep 20. https://www.ncbi.nlm.nih.gov/pubmed/17936786

4) Hauge et al: Properties of the C-terminal tail of human mitochondrial inner membrane protein Oxa1L and its interactions with mammalian mitochondrial ribosomes. J Biol Chem. 2010 Sep 3;285(36):28353-62. doi: 10.1074/jbc.M110.148262. Epub 2010 Jul 2. https://www.ncbi.nlm.nih.gov/pubmed/20601428

5) Brenu et al: Methylation profile of CD4+ T cells in CFS/ME. J. Clin Cell Immunol 5, 228https://www.omicsonline.org/open-access/methylation-profile-of-cd-t-cells-in-chronic-fatigue-syndromemyalgic-encephalomyelitis-2155-9899.1000228.php?aid=27598

6) Rorbach et al: MRM2 and MRM3 are involved in biogenesis of the large subunit of the mitochondrial ribosome. Mol Biol Cell, 2014, 25, 17.

7) Garone et al: Defective MRM2 causes MELAS-like clinical syndrome. Hum Mol Genet, 2017, 26, 21.

8) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns. Plos One 2018, 13, 7.

9) Rorbach et al: The human mitochondrial ribosome recycling factor is essential for cell viability. Nucleic Acids Research, 2008, 36, 18.

10) Kerr et al: Gene expression subtypes in patients with CFS/ME. JID, 2008, 197.

11) Frampton et al: Assessment of a 44 gene classifier for the evaluation of CFS from PBMC gene expression. Plos one, 2011, 6, 3.

AMPD3 in ME

Adenosine monophosphate deaminase (AMPD) converts AMP to inosine monophosphate (IMP).

The AMP deaminase gene family:
AMPD1, muscle (m) isoform
AMPD2, liver (l) cells isoform
AMPD3, erothrocyte (e) isoform

The isoforms are named after their predominant location, but are also expressed in other tissue. Fx. AMPD3 is also expressed in muscles.

The purine nucleotide cycle of muscles consist of the conversion of AMP→IMP→AMP and requires AMP deaminase. Flux through this cycle increases during exercise.

Genomics in ME

A gene variant of AMPD3 has been identified as a risk locus in ME (1):

Slide from. Whole Genome Sequencing and Analysis of ME/CFS

https://www.youtube.com/watch?v=nIJX-Q7w_Z4

Epigenomics in ME

The genes AMPD2 and AMPD3 were epigenetic changed in peripheral blood mononuclear cells (PBMC) from ME patients in two studies (2, 3). Some of the DNA methylations in AMPD2 and AMPD3 were related to quality of life in the ME patients (3). AMPD2 and AMPD3 were differntially methylated in PBMC from ME patient subtypes (4).

Transcriptomics in ME

AMPD3 gene expression was downregulated in biopsies from the vastus lateralis muscle in ME patients (5).

Metabolomics in ME

Metabolic profiling of ME patients showed disturbances in purine metabolism (6, 7, 8). Fx, IMP was decreased in plasma from ME patients (8). 

HDAC3 and AMPD3

Depletion of histone deacetylase 3 (HDAC3) in skeletal muscle in mice causes lower glucose utilization and greater lipid oxidation. AMPD3 is involved in the regulation of the fuel switch (9).

Interestingly, very low density lipoprotein receptor (VLDLR) was found to be up-regulated in the ME muscle biopsies in ref 5. VLDLR is responsible for VLDL uptake into the fiber and is involved in the primary pathway of fatty acid transport in skeletal muscle (5). 

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was down-regulated (5). PFKFB3 belongs to a family of bifunctional proteins that are involved in both the synthesis and degradation of fructose-2,6-bisphosphate, a regulatory molecule that controls glycolysis.

Transducin beta like 1 X-linked receptor 1 (TBL1XR1) was up-regulatede in women and down-regulted in men (5). TBL1XR1 is thought to be a component of both nuclear receptor corepressor (N-CoR) and HDAC3 complexes.

ME is associated with purine and histone deacetylation dysregulation (10). 

References:

1) Whole Genome Sequencing and Analysis of ME/CFS https://www.youtube.com/watch?v=nIJX-Q7w_Z4

2) ) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

3) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns. Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

4) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

5) Pietrangelo et al: Transcription profile analysis of vastus lateralis muscle from patients with chronic fatigue syndrome. Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):795-807. https://www.ncbi.nlm.nih.gov/pubmed/19822097

6) Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N et al (2016) Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A 113:E5472–E5480. https://doi.org/10.1073/pnas.1607571113

7) Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371 https://pubs.rsc.org/en/Content/ArticleLanding/2017/MB/C6MB00600K#!divAbstract

8) Germain et al: Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. 2018 Dec 6;8(4). pii: E90. doi: 10.3390/metabo8040090.
https://www.ncbi.nlm.nih.gov/pubmed/30563204

9) Hong et al: Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. Nat Med. 2017 Feb;23(2):223-234. doi: 10.1038/nm.4245. Epub 2016 Dec 19. https://www.ncbi.nlm.nih.gov/pubmed/27991918

10) Mcgregor et al: Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases Diagnostics (Basel). 2019 Jul 4;9(3). pii: E70. doi: 10.3390/diagnostics9030070. https://www.ncbi.nlm.nih.gov/pubmed/31277442

GPR35, ATPase inhibitor IF1 and ATP synthase subunits

The ME hypothesis "the metabolic trap" tell us that IDO function in immune cells may be compromised (1).

IDO1 and IDO2 catalyze the first step in the kynurenine pathway: The conversion of tryptophan to N-formyl-kynurenine. N-formyl-kynurenine can be converted to kynurenine (KYN). KYN can be further processed to kynurenic acid (KYNA).

ATP synthesis by Complex V is less efficient in ME/CFS cells (2).

ATP synthase (also known as Complex V or F(1)F(o)-ATPase ) consists of several subunits (3). These subunits interact with the ATPase Inhibitory Factor.

The ATPase Inhibitory Factor (ATPIF1) is a master regulator of energy metabolism and of cell survival. (4).

The kynurenic acid responsive GPR35 interacts with ATPIF1. And ATPIF1 interacts with ATP5B (5). 

The gene GPR35 is hypomethylated in peripheral blood mononuclear cells (PBMC) from ME patients (p-value = 6,44E-08, FDR = 0,0029) (6).

ATP synthase subunit beta expression was upregulated in ME patients (7).

Figure from Genecards STRING interaction network (5).


GPR35: G-protein coupled receptor 35; Acts as a receptor for kynurenic acid, an intermediate in the tryptophan metabolic pathway. The activity of this receptor is mediated by G-proteins that elicit calcium mobilization and inositol phosphate production through G(qi/o) proteins (5).

ATPIF1: ATPase inhibitor, mitochondrial; Endogenous F(1)F(o)-ATPase inhibitor limiting ATP depletion when the mitochondrial membrane potential falls below a threshold and the F(1)F(o)-ATP synthase starts hydrolyzing ATP to pump protons out of the mitochondrial matrix. Required to avoid the consumption of cellular ATP when the F(1)F(o)-ATP synthase enzyme acts as an ATP hydrolase. Indirectly acts as a regulator of heme synthesis in erythroid tissues- regulates heme synthesis by modulating the mitochondrial pH and redox potential (5).

ATP5B: ATP synthase subunit beta, mitochondrial; Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk (5).


Is something going on in the ATP5B - ATPIF1 - GPR35 interaction network in  ME?

Further reading: 

Is the kynurenic acid responsive Gpr35 involved in the ME pathomechanism?
http://followmeindenmark.blogspot.com/2019/06/is-kynurenic-acid-responsive-gpr35.html

Complex V is down in ME - does it also explain Electromagnetic Hypersensitivity?
http://followmeindenmark.blogspot.com/2019/07/complex-v-is-down-in-me-does-it-also.html

Complex V is down in ME - does it explain Chemical Intolerance?
http://followmeindenmark.blogspot.com/2019/07/complex-v-is-down-in-me-does-it-explain.html

Mutations in the IDO2 gene and DNA methylations in genes in the NAD/NADP synthesis pathway in ME
http://followmeindenmark.blogspot.com/2019/07/mutations-in-ido2-gene-and-dna.html

CTLA-4 induces IDO and SOCS3 drives degradation of IDO
http://followmeindenmark.blogspot.com/2019/06/ctla-4-induces-ido-and-socs3-drives.html

References:

1) Kashi AA Davis RW and, Phair RD: The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS. Diagnostics (Basel). 2019 Jul 26;9(3). pii: E82. doi: 10.3390/diagnostics9030082. https://www.mdpi.com/2075-4418/9/3/82

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

2) 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

3) Wikipedia: ATP synthase: https://en.wikipedia.org/wiki/ATP_synthase

4) García-Bermúdez J, Cuezva JM.:The ATPase Inhibitory Factor (IF1) is a master regulator of energy metabolism and of cell survival. Biochim Biophys Acta. 2016 Aug;1857(8):1167-1182. doi: 10.1016/j.bbabio.2016.02.004. Epub 2016 Feb 12.
https://www.sciencedirect.com/science/article/pii/S0005272816300238?via%3Dihub#f0020

5) Genecards STRING interaction network, GPR35 https://www.genecards.org/

6) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.
Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

7) Ciregia et al: Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndrome. Transl Psychiatry. 2016 Sep 27;6(9):e904. doi: 10.1038/tp.2016.184.  https://www.nature.com/articles/tp2016184