fredag den 30. november 2018

Bile acid transporter SLCO3A1 and ME

Bile acid transporters maintain bile acid homeostasis.

Solute Carrier Organic Anion Transporter Family Member 3A1 (SLCO3A1) Is a Bile Acid Efflux Transporter in Cholestasis (1).

SLCO3A1 is up-regulated as an adaptive response to cholestasis (1).

Genome-wide association analysis identified a single nucleotide polymorphism (SNP) in SLCO3A1 in ME patients (2).

Epigentic analysis identified that the gene SLCO3A1 (5'UTR) was hypomethylated in peripheral blood mononuclear cells (PBMC) from ME patients. (3).

Metabolomic analysis on plasma from ME patients identified lower levels of (4):

  • glycocholate
  • glycochenodeoxycholate
  • glycolithocholate
  • lithocholate
  • sulfoglycolithocholate
  • taurine

How is SLCO3A1 involved in ME?

Interestingly, bile acids activated receptors regulate innate immunity (5).

References

1) Pan et al. Solute Carrier Organic Anion Transporter Family Member 3A1 Is a Bile Acid Efflux Transporter in Cholestasis. Gastroenterology. 2018 Nov;155(5):1578-1592.e16. doi: 10.1053/j.gastro.2018.07.031. Epub 2018 Jul 29. https://www.ncbi.nlm.nih.gov/pubmed/30063921

2) Schlauch et al: Genome-wide association analysis identifies genetic variations in subjects with ME/CTS. 2016.doi.10.1038/tp.2015.208

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) 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

5) Fiorucci et al. Bile Acids Activated Receptors Regulate Innate Immunity. Front Immunol. 2018 Aug 13;9:1853. doi: 10.3389/fimmu.2018.01853. eCollection 2018.
https://www.ncbi.nlm.nih.gov/pubmed/30150987

onsdag den 28. november 2018

Lipid Transfer Proteins in ME

Lipid metabolism is dysregulated in ME patients (1, 2, 3).

Genes encoding lipid transfer proteins (LTPs) are epigentic changed in peripheral blood mononuclear cells (PBMC) from ME patients (4, 5, 6, 7).

Protein levels of LTPs are changed in the spinal fluid from ME patients (8).

Lipid Transfer Proteins

Within the eukaryotic cell, more than 1000 species of lipids define a series of membranes essential for cell function. Tightly controlled systems of lipid transport underlie the proper spatiotemporal distribution of membrane lipids, the coordination of spatially separated lipidmetabolic pathways, and lipid signaling mediated by soluble proteins that may be localized some distance away from membranes. Alongside the well-established vesicular transport of lipids, non-vesicular transport mediated by a group of proteins referred to as lipid-transfer proteins(LTPs) is emerging as a key mechanism of lipid transport in a broad range of biological processes. More than a hundred LTPs exist in humans and these can be divided into at least ten protein families. LTPs are widely distributed in tissues, organelles and membrane contact sites (MCSs), as well as in the extracellular space. They all possess a soluble and globular domain that encapsulates a lipid monomer and they specifically bind and transport a wide range of lipids (9).







Fig. 5. Lipid-transfer proteins have multiple modes of action (Figure from Chiappariono et al. ref 9)
a, LTPs can transfer lipids between cellular membranes and act as transporters. b, Some LTPs (chaperones) present lipids to an acceptor protein (e.g. enzymes, LTPs, transmembrane (TM) transporters or transcription factors). c, The LTD can be engaged in intramolecular interactions with other domains (illustrated here in purple) or proteins (not illustrated). Binding to the lipid cargo acts as a trigger that induces conformational changes and leads to the activation of signaling. This mechanism is sometimes coupled to the mechanisms described in a and b. LTPs have pleiotropic functions and can modulate lipid homeostasis, signaling and the structural organization of membranes.


Fig. 4. Domain organizations of human lipid-transfer proteins. The members of the ten families of LTPs are displayed.  (Figure from Chiapparino et al. ref 9).

PITPNA, PITPNC1 and PITPNM2 in ME

The genes encoding the phosphatidylinositol transfer proteins PITPNA, PITPNC1 and PITPNM2 were hypomethylated in PBMC from ME patients in Trivedi's study (7). PITPNM2 was hypomethylated in the genic regions: 1stExon, TSS200, TSS1500 and 3'UTR; and also showed changed DNA methylation pattern in 3 other studies (4, 5, 6).

GM2A in ME

A number of LTPs can transfer lipids to downstream enzymes. GM2 ganglioside activator (GM2A) is a lysomal LTP that works as a cofactor for the glycosphingolipid-degrading enzyme beta-hexosaminidase A (HEXA). GM2A is also involved in presentation of antigenic lipids by CD1 to T cells.

The GM2A gene promoter was hypomethylated in ME patients (table S7 in ref 7).

GM2A precursor, number of unique peptides identified in cerebrospinal fluid (table S1 in ref 8):
1) Controls: 12
2) ME patients: 32
3) Post  treatment  Lyme patients:32

HEXA chain precursor, number of unique peptides identified in cerebrospinal fluid (table S1 in ref 8):
1) Controls: 16
2) ME patients: 30
3) Post  treatment  Lyme patients:28


PLTP in ME

The gene encoding phospholipid transfer protein (PLTP) was hypomethylated (TSS1500) in PBMC from ME patients (7).

PLTP (TSS1500) was differentially methylated in PBMC from ME patients subtypes (6).

PLTP precursor, number of unique peptides identified in cerebrospinal fluid (table S1 in ref 8):
1) Controls: 16
2) ME patients: 31
3) Post  treatment  Lyme patients: 26

STARD13 and ME

The gene encoding StAR related lipid transfer domain containing 13 (STARD13) was hypermethylated in genic region 3'UTR and hypomethylated in TSS200 in PBMC from ME patients (7).

STARD13 was differentially methylated in PBMC from ME patients subtypes (6).

This was some of the LTPs involved in ME.

References

1) 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 

2) 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

3) Nagy-Szakal et al: Insights into ME/CFS phenotypes through comprehensive metabolomics. Nat. Sci. Rep, 2018, 8. https://www.nature.com/articles/s41598-018-28477-9

4) de Vega et al: DNA methylation Modifications associated with CFS. PlosOne, 2014, 9, 8. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104757 

5) 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/

6) 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

7) 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

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

9) Chiapparino et al: The orchestra of lipid-transfer proteins at the crossroads between metabolism and signaling. Prog Lipid Res. 2016 Jan;61:30-9. doi: 10.1016/j.plipres.2015.10.004 https://www.ncbi.nlm.nih.gov/pubmed/26658141

fredag den 23. november 2018

Red blood cell deformability, metabolism and extracellular vesicles in ME/CFS

Red blood cell deformability

Red blood cells (RBCs; erythrocytes) are typically biconcave in shape, transport hemoglobin-bound oxygen and are reversibly deformable facilitating trafficking through capillaries. Decreased deformability of RBCs adversely affects tissue oxygenation (1).

RBC deformability is reduced in some ME/CFS patients (2).

Metabolism and red blood cell membrane

The cell membranes in red blood cells are made up of proteins, fats, and carbohydrates. This means that abnormalities in the cell membrane can be a good way to spot disordered metabolism of these nutrients. Issues with producing too much of a certain metabolite, or not being able to break down a nutrient can cause abnormalities in the cell membrane, which lead to irregular shapes of RBCs (2).

Erythrocyte omega-3 index (5.75%) and n-3 PUFA levels are low in individuals with CFS/ME (3).

Extracellular vesicles in sepsis decrease RBC deformability

A growing body of evidence suggests that extracellular vesicles (EVs) play a role in cell-to-cell communication, and are involved in both physiological and pathological processes (4).

A study on mice showed a significant decrease in RBC deformability following sepsis. Extracellular vesicles isolated from the plasma of mice with sepsis significantly decreased deformability of RBCs ex vivo (1).

Extracellular vesicles in blood from ME patients have been analyzed: The amount of EV-enriched fraction was significantly higher in CFS/ME subjects than in healthy controls (HCs) (p = 0.007) and that EVs were significantly smaller in CFS/ME patients (p = 0.014). Circulating EVs could be an emerging tool for biomedical research in CFS/ME. These findings provide preliminary evidence that blood-derived EVs may distinguish CFS/ME patients from HCs (4).

I suggest a pilot study:

ME/CFS vesicles put together with red blood cells from healthy controls. Can microvesicles from ME/CFS patients decrease deformability of RBCs from healthy controls in vitro?




References


1) Subramini et al. Effect of plasma-derived extracellular vesicles on erythrocyte deformability in polymicrobial sepsis. Int Immunopharmacol. 2018 Oct 16;65:244-247. doi: 10.1016/j.intimp.2018.10.011. https://www.ncbi.nlm.nih.gov/pubmed/?term=30340103

2) Erythrocyte Deformability As a Potential Biomarker for Chronic Fatigue Syndrome. Amit K Saha, Brendan R Schmidt, Julie Wilhelmy, Vy Nguyen, Justin Do, Vineeth C Suja, Mohsen Nemat-Gorgani, Anand K Ramasubramanian and Ronald W Davis

Blood 2018 132:4874; doi: https://doi.org/10.1182/blood-2018-99-117260 http://www.bloodjournal.org/content/132/Suppl_1/4874

OMF-funded research: red blood cell deformability in ME/CFS
https://www.omf.ngo/2018/03/21/omf-funded-research-red-blood-cell-deformability-in-me-cfs/

RBC shape, RBC deformability
https://www.omf.ngo/2018/04/04/rbc-shape-rbc-deformability/

3) Castro-Marrero et al: Low omega-3 index and polyunsaturated fatty acid status in patients with chronic fatigue syndrome/myalgic encephalomyelitis.
Prostaglandins, Leukotrienes and Essential Fatty Acids
Volume 139, December 2018, Pages 20-24
https://www.sciencedirect.com/science/article/pii/S095232781830053X

4) Castro-Marrero et al:
Circulating extracellular vesicles as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis: an exploratory pilot study. J Extracell Vesicles. 2018 Mar 22;7(1):1453730. doi: 10.1080/20013078.2018.1453730. eCollection 2018. https://www.ncbi.nlm.nih.gov/pubmed/29696075

tirsdag den 6. november 2018

NPY, AgRP, POMC and NUCB2 in ME

Hypothalamic Pro-opiomelanocortin (POMC) and Neuropeptide Y/Agouti-Related Peptide (NPY/AgRP) neurons are critical nodes of a circuit within the brain that sense key metabolic cues as well as regulate metabolism. Importantly, these neurons retain an innate ability to rapidly reorganize synaptic inputs and electrophysiological properties in response to metabolic state (1).

Exercise (single bout and/or chronic training) increases insulin sensitivity leading to improved insulin stimulated glucose uptake in muscle and reduced basal hepatic glucose production . Within the arcuate nucleus, the melanocortin system is an interface between signals of metabolic state and neural pathways governing energy balance and glucose metabolism. In particular, the orexigenic neuropeptide Y/Agoutirelated peptide (NPY/AgRP) neurons are activated in response to food deprivation, while the anorexigenic proopiomelanocortin (POMC)- expressing cells are inhibited . In addition to contributing to energy balance, the activity of arcuate NPY/AgRP and POMC neurons also have profound effects on glucose metabolism. These changes in cellular activity have been attributed to both native channel properties as well as (re)organization of synaptic connectivity (1 and references herein).

New research shows: Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise (1).

Nesfatin-1 is an 82–amino acid polypeptide derived from the precursor protein nucleobindin 2 (NUCB2), whose processing also yields nesfatin-2 and -3, two peptides with so far unknown functions (2).

Nesfatin-1 is involved in several processes including modulation of gastrointestinal functions, energy metabolism, glucose and lipid metabolism, thermogenesis, mediation of anxiety and depression, as well as cardiovascular and reproductive functions (2).

Use the link to se figure with NUCB2 and the hypothalamus (3): 

As you can se in the figure, the hypothalamus is a key brain area for maintaining glucose and energy homeostasis via the ability of hypothalamic neurons to sense, integrate, and respond to numerous metabolic signals.

Mitochondrial function has emerged as an important component in the regulation of hypothalamic neurons controlling glucose and energy homeostasis. Although the underlying mechanisms are not fully understood, emerging evidence indicates that mitochondrial dysfunction in hypothalamic neurons may contribute to the development of various metabolic diseases (4).

NPY, AgRP, POMC and NUCB2 in ME

NPY precursor, number of unique peptides identified in cerebrospinal fluid (table S1 in ref 5):
1) Controls: 4
2) ME patients: 7
3) Post  treatment  Lyme patients: 6

The plasma level of neuropeptide Y is elevated in ME patiens (6).

POMC, number of unique peptides identified in cerebrospinal fluid (table S1 in ref 5):
1) Controls: 1
2) ME patients: 2 
3) Post  treatment Lyme patients: 1

Some ME patients have single nucleotide plymorphism (SNP) in POMC (7).

The gene POMC (TSS1500, 5'UTR) is hypomethylated in peripheral blood mononuclear cells  (PBMC) from ME patients (8).

NUCB1 precursor, number of unique peptides identified in cerebrospinal fluid (table S1 in ref 5):
1) Controls: 29
2) ME patients: 43
3) Post  treatment Lyme patients: 51

NUCB2 precursor, number of unique peptides identified in cerebrospinal fluid (table S1 in ref 5):
1) Controls: 9
2) ME patients: 8
3) Post  treatment Lyme patients: 13

The gene NUCB2 (5'UTR) is hypomethylated in PBMC from ME patients (8).

The gene NUCB2 (5'UTR) is differentially methylated in PBMC from ME patient subtyes (9).


References

1) He et al: Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise. Mol Metab. 2018 Sep 12. pii: S2212-8778(18)30870-6. doi: 10.1016/j.molmet.2018.08.011 https://www.ncbi.nlm.nih.gov/pubmed/30292523

2) Schalla and Stengel: Current Understanding of the Role of Nesfatin-1. J Endocr Soc. 2018 Oct 1; 2(10): 1188–1206. Published online 2018 Sep 10. doi: [10.1210/js.2018-00246]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169466/

3) Figure from:  Diabetes. 2012 Aug; 61(8): 1920–1922.
and https://www.ncbi.nlm.nih.gov/pubmed/22826310

4) Jin and Diano: Mitochondrial Dynamics and Hypothalamic Regulation of Metabolism. Endocrinology, Volume 159, Issue 10, 1 October 2018, Pages 3596–3604,https://doi.org/10.1210/en.2018-00667 https://academic.oup.com/endo/article-abstract/159/10/3596/5091402?redirectedFrom=fulltext

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

6) Fletcher et al: Plasma neuropeptide Y: a biomarker for symptom severity in chronic fatigue syndrome. Behav Brain Funct. 2010 Dec 29;6:76. doi: 10.1186/1744-9081-6-76 https://www.ncbi.nlm.nih.gov/pubmed/21190576

7) Smith et al: Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue. PHARMACOGENOMICSVOL. 7, NO. 3COLLABORATIVE STUDY: CHRONIC FATIGUE SYNDROME – RESEARCH REPORT
https://www.futuremedicine.com/doi/10.2217/14622416.7.3.387

8) 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

9) 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


onsdag den 31. oktober 2018

TECR (trans-2-enoyl-CoA reductase), VLCFAs and sphingolipids in ME

Very long-chain fatty acids (VLCFAs) are fatty acids (FAs) with a chain-length of ≥22 carbons. Mammals have a variety of VLCFAs differing in chain-length and the number of double bonds. Each VLCFA exhibits certain functions, for example in skin barrier formation, liver homeostasis, myelin maintenance, spermatogenesis, retinal function and anti-inflammation. These functions are elicited not by free VLCFAsthemselves, but through their influences as components of membrane lipids (sphingolipids and glycerophospholipids) or precursors of inflammation-resolving lipid mediators. VLCFAs are synthesized by endoplasmic reticulum membrane-embedded enzymes through a four-step cycle. The most important enzymes determining the tissue distribution of VLCFAs are FA elongases, which catalyze the first, rate-limiting step of the FA elongation cycle. Mammals have seven elongases (ELOVL1-7), each exhibiting a characteristic substrate specificity. Several inherited disorders are caused by mutations in genes involved in VLCFA synthesis or degradation (1).

FAs are elongated by endoplasmic reticulum (ER) membrane-embedded enzymes following their conversion to acyl-CoAs. FA elongation occurs by cycling through a four-step process: condensation, reduction, dehydration and reduction (1).






Fig. 2. from ref 2: Mammalian FA elongation cycle. The FA elongation cycle and enzymes involved in each step are illustrated. In each cycle, acyl-CoA incorporates two carbon units from malonyl-CoA.

In the last reduction step, trans-2-enoyl-CoA is converted to acyl-CoA, which is longer than the original acyl-CoA by two carbons. The trans-2-enoyl-CoA reductase responsible for this reaction is TER (also known as TECR), and the reaction requires NADPH as a cofactor (Moon and Horton, 2003 from ref 2).

TER is involved in both the production of VLCFAs used in the fatty acid moiety of sphingolipids as well as in the degradation of the sphingosine moiety of sphingolipids via S1P (3).

An impaired TER function affects VLCFA synthesis and thereby alters the cellular sphingolipid profile. Maintenance of a proper VLCFA level may be important for neural function (4).

The levels of sphingolipids and glycerolipids in plasma from ME patients are dysregulated (5).

The gene TECR (body) is hypermethylated in peripheral blood mononuclear cells (PBMC) from ME patients. This DNA methylation  is related to quality of life in the ME patients (table S7 in ref 6).

TECR is differentially methylated in PBMC from ME patients subtypes (table S3 in ref 7).

The gene TECR is hypomethylated in PBMC from ME patients (table S4 in ref 8).

TECR is located on chromosome 19 together with mir 639 (9):


Chromosome 19 - NC_000019.10Genomic Context describing neighboring genes

mir 639 is hypomethylated in CD4+ T cells from ME patients (10).




References

1) Akio Kihara: Very long-chain fatty acids: elongation, physiology and related disorders The Journal of Biochemistry, Volume 152, Issue 5, 1 November 2012, Pages 387–395,https://doi.org/10.1093/jb/mvs105
https://academic.oup.com/jb/article/152/5/387/2182729

2) Sassa and Kihara: Metabolism of Very Long-Chain Fatty Acids: Genes and Pathophysiology. Biomol Ther (Seoul). 2014 Mar; 22(2): 83–92.
doi: [10.4062/biomolther.2014.017]

3) Wakashima et al: Dual functions of the trans-2-enoyl-CoA reductase TER in the sphingosine 1-phosphate metabolic pathway and in fatty acid elongation. J Biol Chem. 2014 Sep 5;289(36):24736-48. doi: 10.1074/jbc.M114.571869. Epub 2014 Jul 21.
https://www.ncbi.nlm.nih.gov/pubmed/25049234

4) Abe et al: Mutation for nonsyndromic mental retardation in the trans-2-enoyl-CoA reductase TER gene involved in fatty acid elongation impairs the enzyme activity and stability, leading to change in sphingolipid profile. J Biol Chem. 2013 Dec 20;288(51):36741-9. doi: 10.1074/jbc.M113.493221. Epub 2013 Nov 12.
https://www.ncbi.nlm.nih.gov/pubmed/24220030

5) 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

6) 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/

7) 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

8) 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

mandag den 29. oktober 2018

The role of endoplasmic reticulum-mitochondria contact sites

The contact sites that the endoplasmic reticulum (ER) forms with mitochondria, called mitochondria-associated membranes (MAMs), are a hot topic in biological research, and both their molecular determinants and their numerous roles in several signaling pathways are is continuously evolving (1).


MAMs are now considered as structural platform for an optimal bioenergetics response allowing cellular adaptations to environmental changes. Indeed, the transfer of Ca2+from ER to mitochondria is crucial for the control of mitochondria energy metabolism, since mitochondrial Ca2+ levels control the activity of Krebs cycle’s deshydrogenases and impact ATP synthesis (Fig. (Fig.2).2 from ref 1).

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Object name is 41419_2018_416_Fig2_HTML.jpg
Fig. 2 from ref 1:  Key components and functions of MAMs involved in the control of glucose homeostasis. ER-mitochondria contact sites shelter several components that impact glucose homeostasis either indirectly by regulating mitochondria biology, UPR signaling and autophagy and immune signalling, or more directly by controlling insulin signaling.

Metabolic regulations are tightly coupled with inflammation and immune responses and exacerbated inflammatory responses have been linked to metabolic diseases. ER-mitochondria contact sites were recently found to be an important actor of the cellular anti-viral response (Fig. 2).

During the inflammatory response, NLRP3 and other inflammasome members move to the MAM to coordinate the appropriate response. Calcium sensing receptor (CASR) activates the NLRP3 inflammasome through phospholipase C, which catalyzes IP3 production and thereby induces the release of Ca2 +from the ER (2). TRPM2 is also involved in NLRP3 activation (3).

The distance between the ER and (outer mitochondrial membrane (OMM) is a critical factor in the efficient transfer of Ca2 +. Aside from the spacing between the two organelles, the contact volume is another important parameter in the regulation of Ca2 + signaling. (2) FHIT overexpression enhances the number of these ER–mitochondria hot spots, favoring mitochondrial Ca2 +accumulation and triggering Ca2 +-dependent apoptosis ( [53] in ref 2).

GIMAP5 is a key regulator of hematopoietic integrity and lymphocyte homeostasis. GIMAP5 has a role in maintaining peripheral tolerance and T cell homeostasis in the gut (4). GIMAP5 alsp functions at the MAM (1).

Phosphatidylserine (PS) is synthesized in ER by the exchange of serine for the choline or ethanolamine head-groups of phosphatidylcholines (PC) or phosphatidylethanolamines (PE) by PS synthase-1 and PS synthase−2, which are enriched at MAMs (ref 24 in ref 1). Then, newly-made PS is transferred into mitochondria through MAMs, where it is decarboxylated to PE via PS decarboxylase in mitochondrial inner membrane (ref 25 in ref 1). PS transfer at MAM interface is mediated by oxysterol-binding proteins-related protein 5 (ORP5) and ORP8, which were also localized at MAMs (ref 26 in ref 1).

The above mentioned proteins (CASR, FHIT, GIMAP5, NLRP3, PML, ORP5, ORP8, TRPM2) are encoded by genes which show up with changed DNA methylation pattern in PBMC from ME patients in either one or several studies (5, 6, 7, 8).

References: 

1) Rieusset:  The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: an update. Cell Death Dis. 2018 Mar; 9(3): 388.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844895/

2) Marchi et al: The endoplasmic reticulum–mitochondria connection: One touch, multiple functions. Biochimica et Biophysica Acta (BBA) - Bioenergetics
Volume 1837, Issue 4, April 2014, Pages 461-469

3) Zhong et al: TRPM2 links oxidative stress to NLRP3 inflammasome activation Nat Commun. 2013;4:1611. doi: 10.1038/ncomms2608. https://www.ncbi.nlm.nih.gov/pubmed/23511475

4) GIMAP5: https://www.ncbi.nlm.nih.gov/gene/246774

5) de Vega et al: DNA methylation Modifications associated with CFS. PlosOne, 2014, 9, 8

6) 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/

7) 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

8) 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

søndag den 28. oktober 2018

PACS2 and ME

Endoplasmic reticulum (ER) and mitochondria are tubular organelles with a characteristic “network structure” that facilitates the formation of inter-organellar connections. As a result, mitochondria-associated ER membranes (MAMs), a subdomain of the ER that is tightly linked to and communicates with mitochondria, serve multiple physiological functions including lipid synthesis and exchange, calcium signaling, bioenergetics, and apoptosis. Importantly, emerging evidence suggests that the abnormality and dysfunction of MAMs have been involved in various neurodegenerative disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease (1).



Figure 1: Global view of the architecture/choreography of ER–mitochondria contacts. As depicted, a part of ER tubule and mitochondria form quasi-synaptic structure. Several pairs of integral membrane proteins located on mitochondria and ER important for MERC formation and physical tethering of the organelles were identified, including Mfn1/2 tether, Fis1-Bap31 tether, VAPB-PTPIP51 tether and IP3R-grp75-VDAC1 tripartite complex. The latter is essential for the efficient Ca2+ transfer from the ER to mitochondria. MAM: mitochondria associated ER membrane, OMM = outer mitochondrial membrane, IMM: inner mitochondrial membrane, Mx = matrix, ETC: electron transport chain, TAC: tricarboxylic acid cycle  Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases Transl Neurodegener. 2017;6:21. (ref 1).

Figure 1 shows phosphorin acidic cluster sorting protein 2 (PACS2). PACS2 modulates the Fis1-Bap31 tether (1).

PACS2 is a multifunctionel protein involved in (2): 

  • membrane trafficking
  • MAM-localized ca2+ signaling
  • switching between anabolic and catabolic roles of the MAM
  • p53-p21-dependent cell cycle arrest
  • apoptosis
  • lipid metabolism
  • regulating recycling of the metalloproteinase ADAM17
  • subcellular distribution of calnexin


PACS2 functions as a metabolic switch that integrates traffic and interorganellar communication with nuclear gene expression in response to anabolic or catabolic cues (2).

Viruses can hijack the PACS2 pathway (2).

The gene PACS2 (TSS1500) is differentially methylated in PBMC from ME patients subtypes (3).


References 


1) LIU and Zhu: Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases.
. 2017; 6: 21.
Published online 2017 Aug 23. doi:  10.1186/s40035-017-0092-6
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567882

2) Thomas et al. Caught in the act - protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease.J Cell Sci. 2017 Jun 1;130(11):1865-1876. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482974/

3)  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