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Organelle Homeostasis in Metabolism

The endoplasmic reticulum is a cellular compartment committed to protein and lipid synthesis, maturation and trafficking, as well as calcium homeostasis. Our laboratory is particularly interested in the mechanisms by which this organelle integrates nutrient-sensing with metabolic responses and endocrine networks. Under this umbrella, our focus comprises: a) Organelle interactions and functions in cellular homeostasis control b) Nutrient sensing through ER-resident proteins; c) Regulation of calcium homeostasis in the ER; d) Mechanisms regulating proteostasis.

Chronic and rapid nutrient uptake predisposes cells to nutrient accumulation, which can stress many adaptive systems and drive the development of metabolic diseases. We have identified the ER-resident transcription factor erythroid 2 related factor-1 (Nrf1/Nfe2L1) as a critical sensor and regulator against excessive cholesterol exposure. Our interest lies in understanding the mechanisms by which ER-resident proteins such as Nrf1 sense different nutrients and couple to a broad adaptive program to maintain cellular integrity.

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The endoplasmic reticulum (ER) and mitochondria have dynamic physical and functional interactions at mitochondria-associated membranes (MAMs), which are conserved structures that determine cell survival through the transfer of calcium and other metabolites. In the context of obesity, we find an abnormal increase in MAM formation, contributing to impaired metabolic homeostasis. We are interested in how these inter-organelle interactions, and also mitochondrial ROS production, can shape metabolic regulation.

In the context of obesity, the ER is less capable of storing calcium properly, leading to impaired function of metabolic enzymes. We have shown that proteins that sense and regulate the levels of calcium in the ER, such as STIM1, are altered in liver cells of obese mice. We want to understand the connections and mechanisms that underlie calcium homeostasis and obesity-associated alterations.

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