Journal article
Mu opioid receptor-mediated release of endolysosome iron increases levels of mitochondrial iron, reactive oxygen species, and cell death
NeuroImmune Pharmacology and Therapeutics
14 Sep 2022
Abstract
Abstract
Objectives
Opioids including morphine and DAMGO activate mu-opioid receptors (MOR), increase intracellular reactive oxygen species (ROS) levels, and induce cell death. Ferrous iron (Fe
2+
) through Fenton-like chemistry increases ROS levels and endolysosomes are “master regulators of iron metabolism” and contain readily-releasable Fe
2+
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 Fe
2+
and ROS levels and cell death.
Results
Morphine and DAMGO de-acidified endolysosomes, decreased endolysosome Fe
2+
levels, increased cytosol and mitochondria Fe
2+
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 Fe
2+
and ROS. Opioid-induced efflux of endolysosome Fe
2+
and subsequent Fe
2+
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 Fe
2+
and ROS as well as cell death appear downstream of endolysosome de-acidification and Fe
2+
efflux from the endolysosome iron pool that is sufficient to affect other organelles.
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Details
- Title
- Mu opioid receptor-mediated release of endolysosome iron increases levels of mitochondrial iron, reactive oxygen species, and cell death
- Creators
- Peter W. Halcrow - University of North DakotaNirmal Kumar - University of North DakotaEmily Hao - University of North DakotaNabab Khan - University of North DakotaOlimpia Meucci - Drexel UniversityJonathan D. Geiger - University of North Dakota
- Publication Details
- NeuroImmune Pharmacology and Therapeutics
- Publisher
- De Gruyter
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Other Identifier
- 991020100069904721