HIV-1 gp120- and Morphine-Induced Endolysosome Iron Release Triggers Disruption of the Reactive Species Interactome and Cell Death

Abstract

<b>Abstract ID 25123</b> <b>Poster Board 549</b> Altered iron metabolism is implicated in many neurodegenerative disorders including HIV-1-associated neurocognitive disorders (HAND). Implicated in the pathogenesis of HAND is the HIV-1 coat protein gp120 as well as comorbid substance abuse, which induce iron dysregulation and the formation of reactive species that cause neuronal death. Because HIV-1 proteins and the ingestion of substances of abuse induce oxidative stress, drug-abusing patients are at a greater risk of oxidative stress-induced neuronal injury and HAND. Previous research has studied the individual effects of gp120- and morphine-induced neurotoxicity with a focus on the formation of reactive oxygen species (ROS); however, their combined neurotoxicity and effects on the newly defined reactive species interactome (RSI) remain largely unknown. Endolysosomes are subcellular acidic organelles known for their function in regulating cellular iron metabolism and redox signaling. Recently, we showed that HIV-1 gp120 and morphine cause endolysosome iron dyshomeostasis, yet the impact of impaired endolysosome iron balance on the RSI remains unknown. Here using SH-SY5Y neuroblastoma and U87MG human glioblastoma cells, we found that HIV-1 gp120 and morphine (1) de-acidified endolysosomes, (2) decreased endolysosome Fe²⁺ levels, (3) increased cytosolic and mitochondrial Fe²⁺ levels, (4) increased endolysosome ROS, lipid peroxidation (LPO) and nitric oxide (NO) levels and decreased endolysosome hydrogen sulfide (H₂S) levels, (5) increased cytosolic ROS levels and decreased cytosolic H₂S levels, (6) increased mitochondrial ROS and LPO, and NO levels and decreased mitochondrial H₂S levels and (7) induced cell death; effects blocked by the endolysosome-specific iron chelator deferoxamine. Thus, an increased understanding of the endolysosome Fe²⁺ pool that plays a critical role in regulating inter-organellar iron signaling, in RSI homeostasis, and in contributing to HIV-1 gp120 and morphine neurotoxicity may provide new insight into potential therapeutic targets for HAND progression. Support/Funding Information: [P20GM139759, P30GM100329, U54GM115458, R01MH100972, R01MH105329, R01MH119000, 2R01NS065957, 2R01DA032444]