The ER-mitochondrial Interface in astrocytes during methamphetamine exposure and HIV-1 infection

Early during infection, human immunodeficiency virus 1 (HIV-1) invades the central nervous system (CNS) and can persist for life, despite effective antiretroviral treatment. Infection and activation of residential glial cells leads to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV-associated neurocognitive disorders (HAND). Notably, substance use, including methamphetamine (METH) is disproportionately elevated among people living with HIV-1 and can increase the risk and severity of HAND. Thus, the National Institutes on Drug Abuse have declared HIV-1 and substance use comorbidity as a high research priority. Astrocytes are the most numerous glial cells and provide essential support to neurons. Chronic activation of astrocytes, such as during HAND or METH use disorders, can shift astrocytes to become neurotoxic. Delineating cellular targets to regulate astrocyte function is essential to ensure neuronal fitness during a pathological challenge. Endoplasmic reticulum (ER) and mitochondria contact sites, termed mitochondria-associated ER membranes (MAMs), are key cellular platforms in neuropathology, where calcium dysregulation, unfolded protein response (UPR) sensors, and mitochondrial dysfunction are notable MAM-mediated mechanisms underlying astrocyte dysfunction. We hypothesize that the ER-mitochondria interface may serve as a therapeutic target for astrocyte dysfunction via calcium and non-canonical UPR signaling during HIV-1 and METH pathogenesis. Primary human astrocytes were infected with a pseudotyped HIV-1 and/or exposed to low doses of METH for seven days. Following HIV-1 infection and/or chronic METH exposure, astrocytes had increased mitochondrial respiration, cytosolic calcium flux and protein expression of UPR/MAM mediators. Notably, inositol-requiring enzyme 1α (IRE1α) was prominently upregulated following both HIV-1 infection and chronic METH exposure. Further investigations revealed IRE1α modulates astrocyte mitochondrial respiration, glycolytic function, morphological activation, inflammation, and glutamate uptake. We then investigated a novel METH-binding receptor, trace amine-associated receptor 1 (TAAR1) as a potential upstream regulator to METHinduced UPR/MAM mediator expression. Indeed, selective antagonism of TAAR1 significantly suppressed UPR/MAM protein expression, including IRE1α. Altogether, our findings emphasize the importance and potential therapeutic intervention of UPR/MAM messengers, namely IRE1α and calcium, to combat astrocyte dysfunction, Moreover, TAAR1 may be an upstream target for METH-mediated astrocyte dysfunction.