Biology subjects

Velasco, K. R.

Publications and source records attributed to Velasco, K. R..

4 recordsLinked to original sources

bioRxiv2026

Cholesterol availability drives the assembly of mitochondria-associated ER membranes

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.

cell biology↗

bioRxiv2025

Upregulation of MAM by C99 disrupts ACSL4 activity and phospholipid homeostasis in Alzheimer disease.

The structure and function of cellular and intracellular membranes are critically governed by the fatty acid (FA) composition of phospholipids (PLs), which is dynamically regulated by a network of enzymes that fine-tune lipid species according to cellular demands. In this study, we identify a mechanism through which the formation of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) modulates the activity of the acyl-CoA synthetase long-chain family member 4 (ACSL4), an enzyme that channels polyunsaturated fatty acids (PUFAs) into phosphatidylcholine (PC) via the Lands cycle. Through integrated biochemical, proteomic, and lipidomic analyses in both cellular and animal models, we demonstrate that MAM formation enhances ACSL4 activity, promoting arachidonic acid (AA) activation and its preferential incorporation into PC in concert with the MAM-localized lysophospholipid acyltransferase 4 (LPCAT4). Our findings further uncover an unexpected link between this pathway and the pathogenesis of Alzheimers disease (AD). We show that elevated levels of C99--the {beta}-secretase cleavage product of amyloid precursor protein (APP)--induce MAM remodeling through cholesterol clustering, which in turn activates ACSL4 and alters PC composition. This effect is mirrored in AD models as well as in fibroblasts, neurons, and immune cells derived from both familial and sporadic AD patients, all of which exhibit chronically increased C99 levels, heightened ACSL4 activity, and enrichment of PUFA-containing PC species, leading to lipid imbalance and membrane dysfunction. Together, these results establish MAMs as dynamic lipid-regulatory hubs that coordinate ACSL4-dependent membrane remodeling and highlight the contribution of MAM dysregulation to lipid abnormalities observed in AD.

molecular biology↗

bioRxiv2024

The contribution of mitochondria-associated ER membranes to cholesterol homeostasis

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.

cell biology↗

bioRxiv2019

THE C99 FRAGMENT OF APP REGULATES CHOLESTEROL TRAFFICKING

The link between cholesterol homeostasis and the cleavage of the amyloid precursor protein (APP), and their relationship to the pathogenesis of Alzheimers disease (AD) is still unknown. Cellular cholesterol levels are regulated by a crosstalk between the plasma membrane (PM), where most of the cholesterol resides, and the endoplasmic reticulum (ER), where the protein machinery that regulates cholesterol resides. This crosstalk between PM and ER is believed to be regulated by lipid-sensing peptide(s) that can modulate the internalization of extracellular cholesterol and/or its de novo synthesis in the ER. Our data here indicates that the 99-aa C-terminal fragment of APP (C99), a cholesterol-binding peptide, regulates cholesterol trafficking between the PM and the ER. In AD models, increases in C99 provoke the upregulation of cholesterol internalization and its delivery to the ER, which in turn result into the loss of lipid homeostasis and the appearance of AD signatures, such as higher production of longer forms of amyloid {beta}. Our data suggest a novel role of C99 as mediator of cholesterol disturbances in AD, and as a potential early hallmark of the disease.

molecular biology↗