Title: Impact of a-arrestins on organelle function and cellular metabolism
Abstract:
To survive changes in nutrient availability or stressors, cells rearrange their membrane proteome by stimulating vesicle-mediated protein trafficking. The a-arrestins are master regulators of protein trafficking, helping to selectively relocalize membrane proteins. The best-studied class of membrane protein regulated by the a-arrestins are the amino acid transporters (AATs), which allow uptake of amino acids from the extracellular environment. The loss of a-arrestins causes aberrant retention of amino acid transporters at the plasma membrane, which may lead to excess amino acid accumulation in the cell.
Using metabolomics approaches, we find that intracellular concentrations of select amino acids are increased in cells lacking a-arrestins. For instance, we find that cells lacking a-arrestin Art1, a known regulator of the arginine and lysine transporters Can1 and Lyp1, respectively, have elevated intracellular arginine and lysine. Cells lacking Art1 have fragmented mitochondria with reduced membrane potential and defective cellular respiration. We show that these defects can be restored by negating the cells’ ability to take up arginine and lysine, either by growing them in the absence of arginine and lysine or by deletion of the Can1 and Lyp1 transporters. This defective mitochondrial function is linked to impaired vacuole function. The vacuole proteome and lipid composition are dysregulated in cells lacking a-arrestin Art1, and this contributes to defective mitochondrial function and amino acid imbalances. Our research demonstrates an exciting new link between the maintenance of amino acid homeostasis and regulation of polyphosphate metabolism. Over 80% of cellular arginine is stored in vacuoles, and to increase arginine storage in this organelle, cells lacking Art1 upregulate polyphosphate synthesis to act as a counter ion as evidenced by early studies of polyphosphate. These dramatic shifts in cellular physiology when a-arrestin Art1 is lost help define the interconnection between cellular metabolism and organelle function.
O'Donnell Lab
Friday, November 3rd, 2023
12:00PM
Langley A219B