TAARgeting Astrocyte Mitochondrial Dysfunction during HIV-associated Neuroinflammation and METH Exposure.

Purpose: Methamphetamine (METH) use exacerbates HIV-1 infection, accelerating the severity and onset of HIV-associated neurocognitive disorders (HAND), along with immune dysfunction and resistance to antiretroviral therapy. Neurocognitive impairment is more prevalent in HIV+ METH users than either HIV+ or METH+ alone. A common neurotoxic mechanism during HIV CNS infection is mitochondrial impairment leading to oxidative stress. METH directly and indirectly contributes to mitochondrial impairment; however, the mechanisms regulating mitochondrial homeostasis and overall oxidative burden in astrocytes are not well understood in the context of HIV-associated neuroinflammation and METH abuse. We have reported that astrocyte-trace amine associated receptor 1 (TAAR1) is induced by HAND-relevant stimuli and binds METH, leading to cAMP/calcium signaling and impaired glutamate clearance during HIV. We hypothesize that METH-abuse in HAND modulates astrocyte-TAAR1 levels and activity, regulating astrocyte-mediated neurotoxic outcomes, including mitochondrial damage and increased oxidative burden. Methods: TAAR1-mediated regulation was evaluated with siRNA or the selective inhibitor, EPPTB. Mitochondrial size was assessed by MitoTracker Red™ labeling and fluorescent microscopy. The effects of METH on oxygen consumption were measured by extracellular flux Seahorse assay, while changes in gene expression were measured by real-time PCR, western blotting and WES protein assays respectively. Results: Here we report METH-mediated impairment of astrocyte mitochondrial recycling during prolonged exposure in the context of HIV, including enlarged mitochondrial size, mitofusin recruitment, altered oxygen consumption and increased resulting oxidative burden. Further, astrocyte TAAR1 appears to regulate mitochondrial recycling. Conclusions: TAAR1 may be a valid therapeutic target to ameliorate astrocyte-mediated neurodegeneration in HAND and METH abuse.