Human Immunodeficiency Virus Type 1 and Methamphetamine-Mediated Mitochondrial Damage and Neuronal Degeneration in Human Neurons

Abstract

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 are 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 (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 increase 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 increase oxidative stress, DRP-1 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.

Methamphetamine Augments HIV-1 gp120 Inhibition of Synaptic Transmission and Plasticity in Rat Hippocampal Slices: Implications for Methamphetamine Exacerbation of HIV-Associated Neurocognitive Disorders.

“…Furthermore, a cross-species study demonstrated that HIV in humans and gp120 in mice impaired learning and executive functions which were worsened by Meth abuse in both species [6]. Although exact mechanisms for Meth exacerbation of HIV/gp120-associated neurocognitive impairment remain ambiguous, various possibilities have been proposed including, but are not limited to, oxidative stress [78,79], microglia activation and resultant neural injury [19,38,39], disruption of the blood-brain barrier [80, 81] and synaptodendritic dysfunction and damage in the adult cortex and hippocampus [24,26]. Our results showed the synergic effect of Meth and gp120 on LTP was signi cantly attenuated by Ac-YVAD-CMK, a potent and irreversible inhibitor of the in ammatory enzyme caspase-1 [41].…”

Synergistic Impairment of the Neurovascular Unit by HIV-1 Infection and Methamphetamine Use: Implications for HIV-1-Associated Neurocognitive Disorders

“…This axon injury, in turn, could affect action potential signal transmission [ 112 ] or lead to a reduction in nerve conduction velocity [ 113 ]. Besides, gp120 and Tat in combination with METH induced focal swellings of dendrites and reduced the total length of the neuritic network in human primary neurons [ 50 ]. Data from animal studies suggested that loss or alteration of dendritic spines resulting from METH treatment of HIV-1 gp120 tg mice led to impaired learning and memory [ 40 ].…”

“…Dynamin-related protein 1 (DRP1) is the central molecular player that mediates mitochondrial fission. METH has been found to increase mitochondrial fragmentation through translocation of DRP1 in HIV-1-treated human primary neurons [ 50 ]. The impaired mitophagy detected in the presence of METH in combination with HIV-1 gp120 or Tat proteins in this study suggests its possible association with the accelerated aging observed in HIV-1-infected individuals.…”

Methamphetamine exposure induces neuronal programmed necrosis by activating the receptor‐interacting protein kinase 3 ‐related signalling pathway

“…36,37 METH has been reported to cause mitochondrial dynamics disorder and degeneration in neural cells. [38][39][40] However, it remains unknown whether RIP3 can cause METH-induced programmed necrosis by activating Drp1 to cause increased mitochondrial division.…”

“…Mitochondrial fission dysregulation can produce spherical mitochondria or fragmented mitochondria and induce cristae remodelling, which is characterized by the breakage and disappearance of cristae 36,37 . METH has been reported to cause mitochondrial dynamics disorder and degeneration in neural cells 38‐40 . However, it remains unknown whether RIP3 can cause METH‐induced programmed necrosis by activating Drp1 to cause increased mitochondrial division.…”