Endolysosome Iron Chelation Inhibits HIV-1 Protein-Induced Endolysosome De-Acidification-Induced Increases in Mitochondrial Fragmentation, Mitophagy, and Cell Death.

People with human immunodeficiency virus-1 (PLWH) experience high rates of HIV-1-associated neurocognitive disorders (HANDs); clinical symptoms range from being asymptomatic to experiencing HIV-associated dementia. Antiretroviral therapies have effectively prolonged the life expectancy related to PLWH; however, the prevalence of HANDs has increased. Implicated in the pathogenesis of HANDs are two HIV-1 proteins, transactivator of transcription (Tat) and gp120; both are neurotoxic and damage mitochondria. The thread-like morphological features of functional mitochondria become fragmented when levels of reactive oxygen species (ROS) increase, and ROS can be generated via Fenton-like chemistry in the presence of ferrous iron (Fe). Endolysosomes are central to iron trafficking in cells and contain readily releasable Fe stores. However, it is unclear whether the endolysosome store is sufficient to account for insult-induced increases in levels of ROS, mitochondrial fragmentation, autophagy, and cell death. Using U87MG astrocytoma and SH-SY5Y neuroblastoma cells, we determined that chloroquine (CQ), Tat, and gp120 all (1) de-acidified endolysosomes, (2) decreased endolysosome numbers and increased endolysosome sizes, (3) increased mitochondrial numbers (fragmentation), (4) increased autophagosome numbers, (5) increased autolysosome numbers, (6) increased mitochondrial fragments within endolysosomes, and (7) increased cell death. These effects were all blocked by the endolysosome-specific iron chelator deferoxamine (DFO). Thus, the endolysosome de-acidification-induced release of endolysosome Fe is sufficient to account for inter-organellar signaling events and cell biology consequences of HIV-1 proteins, including mitochondrial fragmentation, autophagy, and cell death.