2021-04-302021-04-302021https://hdl.handle.net/20.500.12503/30606Research Appreciation Day Award Winner - 2021 Graduate School of Biomedical Sciences Oral Presentation - 1st PlacePurpose: Astrocytes are key regulators of central nervous system (CNS) health and neuronal function. However, astrocyte mitochondrial dysfunction, such as induced by HIV-1, threatens the ability of astrocytes to provide the essential metabolic and antioxidant support to neurons. This study examined the endoplasmic reticulum (ER)-mitochondrial interface in response to HIV-1 infection to characterize changes in mitochondrial function, the unfolded protein response (UPR), and the regulation of mitochondria associated membranes (MAMs). We hypothesized that the ER regulates astrocyte mitochondrial function via UPR/MAM signaling during HIV-1 infection. Methods: The effects of chronic HIV-1 infection were examined using pseudotyped HIV-1 to infect primary human astrocytes. Astrocyte mitochondrial function and metabolic status were assessed using Seahorse extracellular flux analyzer while expression of UPR/MAM mediators was determined using protein expression assays. Pharmacological inhibition of the UPR pathways was used to delineate key regulatory mechanisms mediating changes on astrocyte mitochondrial function. Results: Our studies demonstrate increased astrocyte metabolic capacity in response to chronic HIV-1 infection which corresponded to increased expression of UPR/MAM mediators. Moreover, pharmacological inhibition of IRE1α impaired astrocyte mitochondrial activity. Conclusion: These findings illustrate the importance of ER-mitochondria communication in regulating astrocyte mitochondrial function and identify a novel possible mechanism to manipulate the metabolic and antioxidant coupling between astrocytes and neurons during HIV-1 pathogenesis.enpresentation