Mitochondria-associated membranes (MAMs) - molecular organization, cellular functions, and their role - in health and disease

Sep 29, 2026

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Mitochondria-associated membranes (MAMs) are specialized ER–mitochondria contact sites that preserve cellular homeostasis through tightly orchestrated molecular mechanisms. These dynamic interfaces are sustained at 10–50 nm distances by tethering complexes, enabling lipid synthesis and transfer, calcium signaling, metabolic regulation, and quality control via autophagy and mitophagy. Advances in super-resolution microscopy and proteomics link MAM dysfunction to disease mechanisms. The review details how altered MAM spacing impacts Alzheimer’s and Parkinson’s disease and extends relevance to metabolic disorders, cancer, and viral infections, while summarizing emerging therapeutic strategies targeting MAM-associated pathways.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

Molecular organization of MAMs

ER and mitochondrial tethering components

Sigma-1 receptor and signaling regulation

Cellular functions coordinated by MAMs

MAM dysfunction in health and disease

Neurodegeneration (Alzheimer’s and Parkinson’s)

Metabolic disorders, cancer, and viral infections

Therapeutic strategies targeting MAM pathways

REVIEW Mitochondria-associated membranes (MAMs): molecular organization, cellular functions, and their role in health and disease Viet Bui 1, Maryline Santerre 1, Natalia Shcherbik2 and Bassel E Sawaya 1,3,4 1 FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA 2 Department for Cell and Molecular Biology, Rowan-Virtua School of Osteopathic Medicine, Stratford, NJ, USA 3 Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA 4 Department of Neural Cells, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA Keywords calcium signaling; cellular stress responses; ER–mitochondria contact sites; lipid metabolism; mitochondria-associated membranes; neurodegeneration Correspondence B. E. Sawaya, FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, 3307 North Broad Street, Philadelphia, PA 19140, USA Fax: +1 252 707 5948 Tel: +1 215 707 5446 E-mail: [sawaya@temple.edu](sawaya@temple.edu) Viet Bui and Maryline Santerre contributed equally to this article. (Received 18 August 2025, accepted 4 September 2025) doi:10.1002/2211-5463.70121 Mitochondria-associated membranes (MAMs) are specialized contact sites between the endoplasmic reticulum (ER) and mitochondria that maintain cellular homeostasis through precisely orchestrated molecular mechanisms. These dynamic interfaces are maintained at 10–50 nm distances by complex tethering proteins, including the core IP3R–GRP7 5–VDAC1 complex and regulatory proteins, such as the sigma-1 receptor. MAMs coordinate multiple essential cellular processes: lipid synthesis and transfer, calcium signaling, metabolic regulation, and quality control through autophagy and mitophagy. Recent advances in super-resolution microscopy and proteomics have revealed that MAM dysfunction drives pathogenesis across various diseases. In Alzheimer’s disease, disrupted MAM spacing directly affects Ab production and mitochondrial function, while in Parkinson’s disease, a-synuclein accumulation at MAMs impairs phosphatidylserine metabolism and mitochondrial dynamics. Beyond neurodegeneration, MAMs play crucial roles in metabolic disorders, cancer progression, and viral infections. This review provides mechanistic insights into MAM biology, from molecular organization to disease pathogenesis, integrating structural analyses with dynamic visualization approaches. We examine emerging therapeutic strategies targeting MAM-associated pathways and highlight their potential in treating complex diseases. Mitochondria-associated membranes (MAMs) are specialized contact sites that facilitate critical communication between the endoplasmic reticulum (ER) and mitochondria [1] . First observed by Jean Vance in 1990 via electron microscopy [2], these domains were later biochemically deﬁned as hubs for phospholipid Abbreviations AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; AMPK, AMP-activated protein kinase; APP, amyloid precursor protein; ATP, adenosine triphosphate; Ca2+, calcium ion; cART, combination antiretroviral therapy; DRP1, dynamin-related protein 1; ER stress, endoplasmic reticulum stress; ER, endoplasmic reticulum; ER,–mitochondria contacts, endoplasmic reticulum–mitochondria contact sites; ERK, extracellular signal-regulated kinase; GSK3b, glycogen synthase kinase 3 beta; IP3R, inositol 1,4, 5-trisphosphate receptor; IRE1, inositol-requiring enzyme 1; ISR, integrated stress response; MAMs, mitochondria-associated membranes; mPTP, mitochondrial permeability transition pore; mtDNA, mitochondrial DNA; OPA1, optic atrophy 1; PD, Parkinson’s disease; PERK, protein kinase RNA-like ER kinase; PKM2, pyruvate kinase M2; PTPIP51, protein tyrosine phosphatase-interacting protein 51; ROS, reactive oxygen species; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase; UPR, unfolded protein response;

FAQs

What are mitochondria-associated membranes (MAMs) and where are they located?

MAMs are specialized contact sites between the endoplasmic reticulum (ER) and mitochondria, maintained at 10–50 nm distances without membrane fusion.

How do MAMs influence cellular functions?

MAMs coordinate lipid synthesis and transfer, calcium signaling, metabolic regulation, and cellular quality control through autophagy and mitophagy.

How does MAM dysfunction contribute to disease?

MAM dysfunction drives pathogenesis across diseases; for example, disrupted MAM spacing affects amyloid-β production and mitochondrial function in Alzheimer’s disease, while α-synuclein accumulation at MAMs impairs phosphatidylserine metabolism and mitochondrial dynamics in Parkinson’s disease.

Sep 29, 2026

Upload by Stanley