UC San Diego

Methamphetamine, a potent psychostimulant, is a highly addictive drug commonly used by persons living with HIV (PLWH), and its use can result in cognitive impairment and memory deficits long after its use is discontinued. Although the mechanism(s) involved with persistent neurological deficits is not fully known, mitochondrial dysfunction is a key component in methamphetamine neuropathology. Specific mitochondrial autophagy (mitophagy) and mitochondrial fusion and fission are protective quality control mechanisms that can be dysregulated in HIV infection, and the use of methamphetamine can further negatively affect these protective cellular mechanisms. Here, we observed that treatment of human primary neurons (HPNs) with methamphetamine and HIV gp120 and Tat increase dynamin-related protein 1 (DRP1)-dependent mitochondrial fragmentation and neuronal degeneration. Methamphetamine and HIV proteins increased microtubule-associated protein 1 light chain 3 beta-II (LC3B-II) lipidation and induced sequestosome 1 (SQSTM1, p62) translocation to damaged mitochondria. Additionally, the combination inhibited autophagic flux, increased reactive oxygen species (ROS) production and mitochondrial damage, and reduced microtubule-associated protein 2 (MAP2) dendrites in human neurons. N-Acetylcysteine (NAC), a strong antioxidant and ROS scavenger, abrogated DRP1-dependent mitochondrial fragmentation and neurite degeneration. Thus, we show that methamphetamine combined with HIV proteins inhibits mitophagy and induces neuronal damage, and NAC reverses these deleterious effects on mitochondrial function.IMPORTANCE Human and animal studies show that HIV infection, combined with the long-term use of psychostimulants, increases neuronal stress and the occurrence of HIV-associated neurocognitive disorders (HAND). On the cellular level, mitochondrial function is critical for neuronal health. In this study, we show that in human primary neurons, the combination of HIV proteins and methamphetamine increases oxidative stress, DRP1-mediated mitochondrial fragmentation, and neuronal injury manifested by a reduction in neuronal network and connectivity. The use of NAC, a potent antioxidant, reversed the neurotoxic effects of HIV and methamphetamine, suggesting a novel approach to ameliorate the effects of HIV- and methamphetamine-associated cognitive deficits.