NOX2-TRPM2 coupling promotes Zn inhibition of complex III to exacerbate ROS production in a cellular model of Parkinson’s disease.

Publication date: Aug 08, 2024

Reactive oxygen species (ROS) serve vital physiological functions, but aberrant ROS production contributes to numerous diseases. Unfortunately, therapeutic progress targeting pathogenic ROS has been hindered by the limited understanding of whether the mechanisms driving pathogenic ROS differ from those governing physiological ROS generation. To address this knowledge gap, we utilised a cellular model of Parkinson’s disease (PD), as an exemplar of ROS-associated diseases. We exposed SH-SY5Y neuroblastoma cells to the PD-toxin, MPP (1-methyl-4-phenylpyridinium) and studied ROS upregulation leading to cell death, the primary cause of PD. We demonstrate: (1) MPP stimulates ROS production by raising cytoplasmic Ca levels, rather than acting directly on mitochondria. (2) To raise the Ca, MPP co-stimulates NADPH oxidase-2 (NOX2) and the Transient Receptor Potential Melastatin2 (TRPM2) channel that form a positive feedback loop to support each other’s function. (3) Ca exacerbates mitochondrial ROS (mtROS) production not directly, but via Zn. (4) Zn promotes electron escape from respiratory complexes, predominantly from complex III, to generate mtROS. These conclusions are drawn from data, wherein inhibition of TRPM2 and NOX2, chelation of Ca and Zn, and prevention of electron escape from complexes -all abolished the ability of MPP to induce mtROS production and the associated cell death. Furthermore, calcium ionophore mimicked the effects of MPP, while Zn ionophore replicated the effects of both MPP and Ca. Thus, we unveil a previously unrecognized signalling circuit involving NOX2, TRPM2, Ca, Zn, and complex III that drives cytotoxic ROS production. This circuit lies dormant in healthy cells but is triggered by pathogenic insults and could therefore represent a safe therapeutic target for PD and other ROS-linked diseases.

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Concepts Keywords
Driving 1-Methyl-4-phenylpyridinium
Exacerbate 1-Methyl-4-phenylpyridinium
Neuroblastoma Calcium
Parkinson Calcium
Phenylpyridinium Cell Line, Tumor
CYBB protein, human
Humans
Mitochondria
NADPH Oxidase 2
NADPH Oxidase 2
Parkinson Disease
Reactive Oxygen Species
Reactive Oxygen Species
TRPM Cation Channels
TRPM Cation Channels
TRPM2 protein, human
Zinc
Zinc

Semantics

Type Source Name
disease MESH Parkinson’s disease
disease MESH neuroblastoma
drug DRUGBANK Coenzyme M
drug DRUGBANK Oxygen
disease MESH death
disease MESH pathological processes
drug DRUGBANK Hydrogen peroxide
drug DRUGBANK L-Cysteine
disease MESH cardiovascular diseases
disease MESH neurodegenerative disorders
drug DRUGBANK Spinosad
drug DRUGBANK Calcium
drug DRUGBANK Adenosine-5-Diphosphoribose
drug DRUGBANK Acetylcysteine
drug DRUGBANK Acetic acid
drug DRUGBANK Ethylenediamine
drug DRUGBANK Trihexyphenidyl
drug DRUGBANK Tetracycline
drug DRUGBANK Palmitic Acid
disease MESH obesity
drug DRUGBANK Apocynin
drug DRUGBANK Pentetic acid
drug DRUGBANK Proline
drug DRUGBANK Albendazole
drug DRUGBANK Human Serum Albumin
drug DRUGBANK Zinc
disease MESH oxidative stress
drug DRUGBANK Pentaerythritol tetranitrate
drug DRUGBANK Dimethyl sulfoxide
disease MESH pathogenesis
drug DRUGBANK Dopamine
drug DRUGBANK Indoleacetic acid
disease MESH metabolic diseases
drug DRUGBANK Streptomycin
drug DRUGBANK L-Glutamine
drug DRUGBANK Methylergometrine
drug DRUGBANK L-Lysine
drug DRUGBANK Iodide
drug DRUGBANK Chloride ion
drug DRUGBANK Anthranilic acid
drug DRUGBANK Pyrithione
drug DRUGBANK ACETOPHENONE
drug DRUGBANK Zinc chloride
drug DRUGBANK Rifampicin
drug DRUGBANK Poloxamer 188
drug DRUGBANK Sodium lauryl sulfate
drug DRUGBANK Flunarizine
drug DRUGBANK Tromethamine
drug DRUGBANK Esomeprazole
pathway KEGG Parkinson disease
drug DRUGBANK NADH
disease MESH parkinsonism
disease MESH Neuroinflammation
drug DRUGBANK Dextrose unspecified form
pathway KEGG Apoptosis
drug DRUGBANK Rotenone
drug DRUGBANK Iron
drug DRUGBANK Clioquinol
disease MESH Stroke
disease MESH polyneuropathy
disease MESH ischemia
disease MESH Tumor

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