Table 1 Overview of the main MAMs connector proteins and their involvement in ALS or HMSN diseases

From: Endoplasmic reticulum and mitochondria in diseases of motor and sensory neurons: a broken relationship?

 

Identification/role at MAMs

Pathogenic role

Tethering proteins complexes

 MFN1/2

MFN1 and MFN2 are dynamin-related GTPases which contribute to the mitochondrial fusion process127. Originally identified on the outer mitochondrial membrane, MFN2 has also been observed on the outside of the ER22. Homodimers (MFN2–MFN2) or heterodimers (MFN2–MFN1) can form between the ER and the mitochondria. The p21Ras-binding domain of MFN2 could be important in MFN2–MFN2 interaction and ER–mitochondria coupling128. Deletion of MFN2 affects mitochondria–ER contacts. Whether MFN2 is a positive or a negative regulator of MAMs formation is still a matter of debate17,43,44,45

Mutations leading to amino acid substitutions in the MFN2 protein, or causing a decrease in MFN2 level, have been associated to several diseases including CMT2A/HMSN2A129, type 2 diabetes, and obesity, as well as Parkinson’s disease130

VAPB

VAPB is an integral ER protein, which binds the mitochondrial PTPIP5123. Overexpression of VAPB or PTPIP51 increases the number of ER–mitochondria contacts, whereas downregulation of these proteins diminishes those contacts23,53

P56S mutation of VAPB causes a familial form of ALS (ALS8), and VAPB–PTPIP51 binding is defective in models of ALS53

 PTPIP51

  

Linkers regulating calcium exchange

 IP3R3

IP3R3 is maintained in close proximity with the mitochondrial VDAC1 by interacting with the GRP75 chaperone which links these two proteins in MAMs131. This complex facilitates the transfer of calcium from the ER towards the mitochondrial inter-membrane space6. In CHO cells, knockdown of the ER-located protein IP3R specifically reduces mitochondrial calcium content24, whereas its stimulation with a selective agonist increases ER calcium flux and calcium uptake by the mitochondria21. Knockdown of GRP75 decreases the transfer of calcium between the two organelles132

Altered VDAC1 function and/or localization have been observed in ALS and HMSN33,35,55

  GRP75

  

 VDAC1

  

Linkers implicated in induction of mitochondria-induced apoptosis

 BAP31

Interaction between the ER-resident protein BAP31 and the mitochondrial fission protein FIS1 recruits procaspase-8 and initiates BAP31 cleavage followed by ER calcium release25. Resulting increase in mitochondrial calcium can trigger pro-apoptotic release of cytochrome c

The roles of these factors in motoneuron disease and in HMSNs remain to be explored

 FIS1

  

 PACS-2

The knockdown of PACS-2 uncouples mitochondria from the ER. PACS-2 downregulation induces BAP31 cleavage-dependent cell death, which suggests an antiapoptotic role of this factor. Its exact function at MAMs remains unclear26

 
  1. ALS amyotrophic lateral sclerosis, BAP31 B-cell receptor-associated protein 31, CHO Chinese hamster ovary, ER endoplasmic reticulum, FIS1 mitochondrial fission 1 protein, GRP75 75 kDa glucose-regulated protein, HMSN hereditary motor and sensory neuropathy, IP3R3 inositol 1,4,5 tri-phosphate receptor type 3, MAM mitochondria-associated membrane, MFN1/2 Mitofusin 1 and 2, PACS-2 phosphofurin acidic cluster sorting protein 2, PTPIP51 protein tyrosine phosphatase interacting protein 51, VAPB vesicle-associated membrane protein-associated protein B, VDAC1 voltage-dependent anion channel 1
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