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).

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

https://www.sciencedirect.com/science/article/pii/S0005272813001850?via%3Dihub

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