Cholesterol availability drives the assembly of mitochondria-associated ER membranes

Abstract

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAM domains, or MAMs) are transient lipid raft domains of the ER that coordinate multiple cellular metabolic pathways and the ER-mitochondria communication. However, the mechanisms that drive their formation remain poorly understood. Here, we reveal that MAM assembly is dynamically regulated by the availability of plasma membrane (PM) cholesterol. We show that cholesterol delivered through high-density lipoproteins (HDLs) via the scavenger receptor class B type 1 (SR-B1) pathway is rapidly redistributed from the PM to the ER, where increased cholesterol availability promotes the assembly of MAM domains. In turn, MAM formation promotes the communication between the ER and mitochondria, the esterification of excess cholesterol and the suppression of cholesterol biosynthesis. Disruption of MAMs uncouples these responses, altering cholesterol trafficking and metabolic adaptation to extracellular cholesterol. Our findings identify MAM as a dynamic metabolic regulator that translates changes in extracellular lipoprotein availability into coordinated intracellular metabolic responses and cellular adaptation.

Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer
Michal Cagalinec, Adnan Mohd, Silvia Borecka +18
Biochimica et Biophysica Acta - Molecular Cell Research28 Sep 2026Peer-reviewedCC BY 4.0Full text14 citedNeuroscienceHAL
Integration of bulk and single-cell transcriptomics via the Scissor algorithm reveals APOE-dependent cholesterol metabolic reprogramming in macrophages associated with osimertinib resistance in non-small cell lung cancer
Zhiyuan Gong, Zhao Gao, Jiachang Zhang +5
Frontiers in Immunology9 Nov 2026Peer-reviewedCC BY 4.0ImmunologyFrontiersCrossref
Formin Is a Processive Motor that Requires Profilin to Accelerate Actin Assembly and Associated ATP Hydrolysis
Stéphane Romero, Christophe Le Clainche, Dominique Didry +3
Cell2 Oct 2026Peer-reviewedLicence not statedFull text565 citedCell biologyHAL
A Draft Genome Assembly of Argania spinosa Provides Insights into Lipid Metabolism-Associated Genes and Repeat-Rich Genome Architecture
My Abdelmajid Kassem, Naoufal Lakhssassi, Dounya Knizia +2
Plants (Basel, Switzerland)26 Sep 2026Peer-reviewedCC BYFull textPlant biologyEurope PMC
Identification and validation of cholesterol homeostasis and NK cell-associated predictive and therapeutic models for Coronary atherosclerotic heart disease patients with ST-elevated myocardial infarction: Insights from artificial intelligence and multi-omics
Xuemei Chen, Yifan Zhao, Xixi Guo +5
Computational Biology and Chemistry14 May 2026Peer-reviewedCC BY-NC-ND7 citedImmunologyOpenAlex

Cite

BibTeX RIS

BibTeX

@misc{uceda2026cholesterol,
  title = {{Cholesterol availability drives the assembly of mitochondria-associated ER membranes}},
  author = {M Uceda and K Kabra and A.C Ferre and L Serrano-Cuñarro and N Gomez-Lopez and M Pera and D Larrea and R.R Agrawal and K.A Tamucci and C Anton-Barros and T.D Yun and K.R Velasco and E.A Schon and J Montesinos and E Area-Gomez},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.29.762740},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.29.762740v1},
  note = {CC BY-ND},
}

RIS

TY  - UNPB
TI  - Cholesterol availability drives the assembly of mitochondria-associated ER membranes
AU  - M Uceda
AU  - K Kabra
AU  - A.C Ferre
AU  - L Serrano-Cuñarro
AU  - N Gomez-Lopez
AU  - M Pera
AU  - D Larrea
AU  - R.R Agrawal
AU  - K.A Tamucci
AU  - C Anton-Barros
AU  - T.D Yun
AU  - K.R Velasco
AU  - E.A Schon
AU  - J Montesinos
AU  - E Area-Gomez
PY  - 2026
DA  - 2026/10/29
PB  - bioRxiv
DO  - 10.64898/2026.10.29.762740
UR  - https://www.biorxiv.org/content/10.64898/2026.10.29.762740v1
AB  - Mitochondria-associated endoplasmic reticulum (ER) membranes (MAM domains, or MAMs) are transient lipid raft domains of the ER that coordinate multiple cellular metabolic pathways and the ER-mitochondria communication. However, the mechanisms that drive their formation remain poorly understood. Here, we reveal that MAM assembly is dynamically regulated by the availability of plasma membrane (PM) cholesterol. We show that cholesterol delivered through high-density lipoproteins (HDLs) via the scavenger receptor class B type 1 (SR-B1) pathway is rapidly redistributed from the PM to the ER, where increased cholesterol availability promotes the assembly of MAM domains. In turn, MAM formation promotes the communication between the ER and mitochondria, the esterification of excess cholesterol and the suppression of cholesterol biosynthesis. Disruption of MAMs uncouples these responses, altering cholesterol trafficking and metabolic adaptation to extracellular cholesterol. Our findings identify MAM as a dynamic metabolic regulator that translates changes in extracellular lipoprotein availability into coordinated intracellular metabolic responses and cellular adaptation.
SN  - 2692-8205
ER  -

Abstract

Related

Cite