What proteins are present in the mitochondria-associated membrane (MAM)?

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Mitochondria-Associated Membrane (MAM) Proteins

The mitochondria-associated membrane (MAM) contains a diverse array of structural, regulatory, and functional proteins that mediate ER-mitochondria interactions, including mitofusins (Mfn1/Mfn2), inverted formin 2, Drp1 receptor proteins (Fis1, mitochondrial dynamics proteins of 49 and 51 kDa, mitochondrial fission factor), Dynamin 2, and various chaperones and calcium-handling proteins.

Structural and Tethering Proteins

The MAM represents physical contact sites between the endoplasmic reticulum and mitochondrial outer membrane, with specific proteins creating and maintaining these connections 1:

Mitochondrial Fusion Proteins

  • Mitofusin-2 (Mfn2) localizes to the outer mitochondrial membrane and serves as a key tethering protein at MAM sites 1, 2
  • Mitofusin-1 (Mfn1) also participates in outer membrane regulation 1
  • Optic atrophy protein 1 (Opa1) regulates the inner mitochondrial membrane 1

Fission Machinery Components

  • Inverted formin 2 (ER-localized) mediates ER-actin interactions to create constriction sites at MAMs before Drp1 recruitment 1
  • Dynamin-related protein 1 (Drp1) is recruited from cytosol to the outer mitochondrial membrane at MAM sites 1, 2
  • Mitochondrial fission protein (Fis1) serves as a Drp1 receptor protein 1
  • Mitochondrial dynamics proteins of 49 and 51 kDa function as additional Drp1 receptors 1
  • Mitochondrial fission factor acts as another Drp1 receptor 1
  • Dynamin 2 works with Drp1 to form ring-like structures for membrane splitting 1

Regulatory and Signaling Proteins

Multiple regulatory proteins coordinate MAM functions 2, 3:

  • Sigma-1 receptor (S1R) regulates ER-mitochondria association 2, 4
  • Presenilin-1 (PS1) participates in MAM structure 2
  • Protein kinase R (PKR)-like ER kinase (PERK) localizes to MAMs and regulates ER stress responses 2, 3
  • Parkin contributes to MAM regulation 2
  • Cyclophilin D (CypD) is present at MAM sites 2
  • DJ-1 participates in MAM functions 2
  • PTEN-induced putative kinase 1 (PINK1) localizes to MAMs 2
  • α-synuclein (α-syn) is found at MAM regions 2

Calcium Handling and Chaperone Proteins

The MAM is enriched in proteins that regulate calcium exchange between organelles 4, 5:

  • Glucose-related protein 75 (Grp75) functions as a molecular chaperone at MAMs 2, 4
  • Calnexin regulates ER-mitochondria association 4
  • Calreticulin participates in MAM regulation 4
  • ERp44 is present at MAM sites 4
  • ERp57 functions at the MAM 4
  • Inositol 1,4,5-trisphosphate receptors mediate calcium transfer 3

Metabolic and Lipid Synthesis Proteins

The MAM contains high concentrations of lipid metabolism enzymes 6, 5:

  • Phosphatidylethanolamine N-methyltransferase-2 serves as a specific MAM marker protein 6
  • Diacylglycerol acyltransferase is enriched 2.2-3.4-fold in MAM compared to ER 6
  • Acyl-coenzyme A:cholesterol acyltransferase shows similar enrichment 6
  • Phosphatidylserine synthase (base exchange enzyme) is concentrated at MAMs 6
  • Microsomal triacylglycerol transfer protein is present for lipoprotein assembly 6
  • ER oxidoreductin 1 (Ero1) participates in MAM functions 2

Additional Structural Proteins

Several other proteins contribute to MAM architecture and function 2, 3:

  • FUN14 domain containing 1 (Fundc1) localizes to MAMs 2
  • Vesicle-associated membrane-protein-associated protein B (VAPB) is present at MAM sites 2
  • Phosphofurin acidic cluster sorting protein 2 (PACS-2) regulates MAM formation 2, 3
  • Receptor expression-enhancing protein 1 (REEP1) participates in MAM structure 2

Yeast-Specific MAM Complex (ERMES)

In yeast, the ER-mitochondria encounter structure (ERMES) forms the core MAM complex 1:

  • Mdm10 (mitochondrial outer membrane protein) 1
  • Mdm34 (mitochondrial outer membrane protein, requires ubiquitination by Rsp5 E3 ligase for mitophagy involvement) 1
  • Mmm1 (ER membrane protein) 1
  • Mdm12 (peripheral membrane protein) 1

Functional Context

These MAM proteins collectively regulate critical cellular processes including calcium exchange between ER and mitochondria, lipid synthesis and transfer, mitochondrial dynamics (fission and fusion), autophagosome formation, and metabolic signaling 1, 4, 5. The MAM represents a specialized subdomain with distinct proteome and biochemical properties compared to bulk ER 6, 5.

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

4
Research

MAM: more than just a housekeeper.

Trends in cell biology, 2009

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