The contribution of mitochondria-associated ER membranes to cholesterol homeostasis

Montesinos, J.; Kabra, K.; Uceda, M.; Larrea, D.; Agrawal, R. R.; Tamucci, K.; Pera, M.; Ferre, A. C.; Gomez-Lopez, N.; Yun, T. D.; Velasco, K. R.; Schon, E. A.; Area-Gomez, E.

doi:10.1101/2024.11.11.622945

bioRxiv · 10.1101/2024.11.11.622945

The contribution of mitochondria-associated ER membranes to cholesterol homeostasis

Montesinos, J.·Kabra, K.·Uceda, M.·Larrea, D.·Agrawal, R. R.·Tamucci, K.·Pera, M.·Ferre, A. C.·Gomez-Lopez, N.·Yun, T. D.·Velasco, K. R.·Schon, E. A.·Area-Gomez, E.

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Abstract

Cellular demands for cholesterol are met by a balance between its biosynthesis in the endoplasmic reticulum (ER) and its uptake from lipoproteins. Cholesterol levels in intracellular membranes form a gradient maintained by a complex network of mechanisms including the control of the expression, compartmentalization and allosteric modulation of the enzymes that balance endogenous and exogenous sources of cholesterol. Low-density lipoproteins (LDLs) are internalized and delivered to lysosomal compartments to release their cholesterol content, which is then distributed within cellular membranes. High-density lipoproteins (HDLs), on the other hand, can transfer their cholesterol content directly into cellular membranes through the action of receptors such as the scavenger receptor B type 1 (SR-B1; gene SCARB1). We show here that SR-B1-mediated exogenous cholesterol internalization from HDL stimulates the formation of lipid-raft subdomains in the ER known as mitochondria-associated ER membranes (MAM), that, in turn, suppress de novo cholesterol biosynthesis machinery. We propose that MAM is a regulatory hub for cholesterol homeostasis that offers a novel dimension for understanding the intracellular regulation of this important lipid.

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Montesinos, J., Kabra, K., Uceda, M., Larrea, D., Agrawal, R. R., Tamucci, K., Pera, M., Ferre, A. C., Gomez-Lopez, N., Yun, T. D., Velasco, K. R., Schon, E. A., Area-Gomez, E.. 2024-11-11. The contribution of mitochondria-associated ER membranes to cholesterol homeostasis. https://doi.org/10.1101/2024.11.11.622945

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