Opioid Modulation of Neuronal Iron and Potential Contributions to NeuroHIV

Nash, Bradley; Irollo, Elena; Brandimarti, Renato; Meucci, Olimpia

doi:10.1007/978-1-0716-0884-5_13

Cited by 8 publications

(4 citation statements)

References 137 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A defining characteristic of endolysosomes is their acidic lumen and the luminal pH is linked to iron homeostasis; inhibiting endolysosome acidity triggers iron dysregulation [ 28 , 33 , 34 ]. Previously, we reported using U87MG astrocytoma cells and primary cultures of rat cerebral cortical neurons that morphine through activation of MORs and Gαi protein signaling decreased levels of endolysosome Fe 2+ , increased levels of cytosolic Fe 2+ , and led to increased levels of ferritin heavy chain [ 35 , 36 ]. However, it remains unclear whether opioids working through MORs cause sufficient changes in levels of Fe 2+ to affect mitochondrial function and cell death.…”

Section: Introductionmentioning

confidence: 99%

Mu opioid receptor-mediated release of endolysosome iron increases levels of mitochondrial iron, reactive oxygen species, and cell death

Halcrow

Kumar

Hao

et al. 2022

NeuroImmune Pharmacology and Therapeutics

Self Cite

View full text Add to dashboard Cite

Objectives Opioids including morphine and DAMGO activate mu-opioid receptors (MOR), increase intracellular reactive oxygen species (ROS) levels, and induce cell death. Ferrous iron (Fe2+) through Fenton-like chemistry increases ROS levels and endolysosomes are “master regulators of iron metabolism” and contain readily-releasable Fe2+ stores. However, mechanisms underlying opioid-induced changes in endolysosome iron homeostasis and downstream-signaling events remain unclear. Methods We used SH-SY5Y neuroblastoma cells, flow cytometry, and confocal microscopy to measure Fe2+ and ROS levels and cell death. Results Morphine and DAMGO de-acidified endolysosomes, decreased endolysosome Fe2+ levels, increased cytosol and mitochondria Fe2+ and ROS levels, depolarized mitochondrial membrane potential, and induced cell death; effects blocked by the nonselective MOR antagonist naloxone and the selective MOR antagonist β-funaltrexamine (β-FNA). Deferoxamine, an endolysosome-iron chelator, inhibited opioid agonist-induced increases in cytosolic and mitochondrial Fe2+ and ROS. Opioid-induced efflux of endolysosome Fe2+ and subsequent Fe2+ accumulation in mitochondria were blocked by the endolysosome-resident two-pore channel inhibitor NED-19 and the mitochondrial permeability transition pore inhibitor TRO. Conclusions Opioid agonist-induced increases in cytosolic and mitochondrial Fe2+ and ROS as well as cell death appear downstream of endolysosome de-acidification and Fe2+ efflux from the endolysosome iron pool that is sufficient to affect other organelles.

show abstract

Section: Introductionmentioning

confidence: 99%

Mu opioid receptor-mediated release of endolysosome iron increases levels of mitochondrial iron, reactive oxygen species, and cell death

Halcrow

Kumar

Hao

et al. 2022

NeuroImmune Pharmacology and Therapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…De cits in extinction of morphine CPP have been observed in the HIV-1 transgenic rat which expresses 7 of 9 HIV-1 viral proteins (Reid et al, 2001), though this model re ects consequences of protein exposure rather than infection. This may suggest generalized impairments in extinction across classes of rewards, though opioids likely interact with HIV to dysregulate cognitive function through discrete mechanisms from psychostimulants (Giacometti and Barker, 2019; Blackard and Sherman, 2021; Cirino and McLaughlin, 2021;Nash et al, 2021). Although the magnitude of reinstatement did not differ, de cits in extinction in HIV-1 infected mice were re ected in the reinstatement session, with overall greater time in the reward-paired chamber in HIV-1 infected mice than in sham counterparts.…”

Section: Discussionmentioning

confidence: 99%

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation

Barker,

Buck,

Xie

et al. 2023

Preprint

View full text Add to dashboard Cite

Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between HIV infection and cocaine use disorder is likely bidirectional, with cocaine use directly impacting immune function while HIV infection alters addiction-related behavior. To better characterize the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilized a humanized mouse model to investigate the outcomes of HIV-1 infection on cocaine-related behaviors in a conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection selectively impaired cocaine CPP extinction without effecting reinstatement or cocaine seeking under conflict were observed. Behavioral alterations were accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes were observed in both mouse and human cytokines, including HIV-induced reductions in mouse IL-1α and G-CSF and human TNFα, and cocaine induced alterations in mouse GM-CSF. Together these data provide new insights into the unique neurobehavioral outcomes of HIV infection and cocaine exposure and how they interact to effect immune responses.

show abstract

“…Several recent studies suggest that opioid signaling may contribute to structural and functional deficits in central nervous system neurons by modulating neuronal iron metabolism, as reviewed in (Nash et al 2021 ). We built from this foundation to better understand the molecular players involved and identified the endolysosomal iron transporter DMT1 as a key component of this process.…”

Section: Discussionmentioning

confidence: 99%

“…Although HIV infection can be well-controlled by antiretroviral therapies, people living with HIV often develop mild to moderate cognitive impairment that can disrupt their daily life (Saylor et al 2016 ). Our group and others have reported that HIV infection and common comorbidities like opioid use are associated with dysregulated iron metabolism in the brain, which could be an important factor that leads to cognitive impairment in people with HIV (Pitcher et al 2014 ; Nash et al 2021 ).…”

Section: Introductionmentioning

confidence: 96%

The Endolysosomal Transporter DMT1 is Required for Morphine Regulation of Neuronal Ferritin Heavy Chain

Irollo,

Nash,

Luchetta

et al. 2023

J Neuroimmune Pharmacol

Self Cite

View full text Add to dashboard Cite

NeuroHIV and other neurologic disorders present with altered iron metabolism in central nervous system neurons. Many people with HIV also use opioids, which can worsen neuroHIV symptoms by further dysregulating neuronal iron metabolism. Our previous work demonstrated that the μ-opioid agonist morphine causes neuronal endolysosomes to release their iron stores, and neurons respond by upregulating ferritin heavy chain (FHC), an iron storage protein associated with cognitive impairment in neuroHIV. Here, we investigated if this process required divalent metal transporter 1 (DMT1), a well-known iron transporter expressed on endolysosomes. We first optimized conditions to detect DMT1 isoforms (DMT1 1B ± iron responsive element) using fluorescently labeled rat DMT1 constructs expressed in HEK-293 cells. We also expressed these constructs in primary rat cortical neurons to compare their expression and subcellular distribution with endogenous DMT1 isoforms. We found endogenous DMT1 isoforms in the cytoplasm that colocalized with lysosomal-associated protein 1 (LAMP1), a marker of endolysosomes. Next, we blocked endogenous DMT1 isoforms using ebselen, a potent pharmacological inhibitor of DMT1 iron transport. Ebselen pre-treatment blocked morphine’s ability to upregulate FHC protein, suggesting this pathway requires DMT1 iron transport from endolysosomes. This was further validated using viral-mediated genetic silencing of DMT1±IRE in cortical neurons, which also blocked FHC upregulation in the presence of morphine. Overall, our work demonstrates that the μ-opioid agonist morphine utilizes the endolysosomal iron transporter DMT1 to modulate neuronal cellular iron metabolism, upregulate FHC protein, and contribute to cognitive decline in neuroHIV. Graphical Abstract Morphine requires DMT1 to upregulate neuronal FHC. Cortical neurons treated with morphine release their endolysosomal iron stores to the cytoplasm and upregulate FHC, an iron storage protein associated with dendritic spine deficits and cognitive impairment in neuroHIV. This pathway requires the endolysosomal iron transporter DMT1, as pharmacological and genetic inhibitors of the transporter completely block morphine’s ability to upregulate FHC. Created with BioRender.com.

show abstract

Opioid Modulation of Neuronal Iron and Potential Contributions to NeuroHIV

Cited by 8 publications

References 137 publications

Mu opioid receptor-mediated release of endolysosome iron increases levels of mitochondrial iron, reactive oxygen species, and cell death

Mu opioid receptor-mediated release of endolysosome iron increases levels of mitochondrial iron, reactive oxygen species, and cell death

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation

The Endolysosomal Transporter DMT1 is Required for Morphine Regulation of Neuronal Ferritin Heavy Chain

Contact Info

Product

Resources

About