Prolonged treatment with mevalonolactone induces oxidative stress response with reactive oxygen species production, mitochondrial depolarization and inflammation in human glioblastoma U-87 MG cells

Rossella Gratton, Paola Maura Tricarico, Fulvio Celsi, Sergio Crovella

Research output: Contribution to journalArticle

Abstract

Mevalonate pathway impairment has been observed in diverse diseases, including Mevalonate Kinase Deficiency (MKD). MKD is a hereditary auto-inflammatory disorder, due to mutations at mevalonate kinase gene (MVK), encoding mevalonate kinase (MK) enzyme. To date, the most accredited MKD pathogenic hypothesis suggests that the typical MKD phenotypes might be due to a decreased isoprenoid production rather than to the excess and accumulation of mevalonic acid, as initially supported. Nevertheless, recent studies provide clear evidences that accumulating metabolites might be involved in MKD pathophysiology by exerting a toxic effect. Our work aims at describing the effects of accumulating mevalonolactone, mostly produced by a dehydration reaction due to mevalonic acid accumulation, using an in vitro cellular model mimicking the glial component of the central nervous system (human glioblastoma U-87 MG cells). In order to mimic its progressive increase, occurring during the disease, U-87 MG cells have been treated repeatedly with growing doses of mevalonolactone, followed by the assessment of oxidative stress response (evaluated by measuring SOD2 and HemeOX expression levels), ROS production, mitochondrial damage and inflammatory response (evaluated by measuring IL1B expression levels). Our results suggest that protracted treatments with mevalonolactone induce oxidative stress with augmented ROS production and mitochondrial damage accompanied by membrane depolarization. Furthermore, an increment in IL1B expression has been observed, thus correlating the accumulation of the metabolite with the development of a neuroinflammatory response. Our experimental work suggests to reconsider the presence of a possible synergy between the two major MKD pathogenic hypotheses in attempt of unravelling the different pathogenic pathways responsible for the disease.

Original languageEnglish
Pages (from-to)233-237
Number of pages5
JournalNeurochemistry International
Volume120
DOIs
Publication statusPublished - Nov 1 2018

Fingerprint

Mevalonate Kinase Deficiency
Glioblastoma
Reactive Oxygen Species
Oxidative Stress
mevalonate kinase
Inflammation
Mevalonic Acid
Poisons
Terpenes
Dehydration
Neuroglia
mevalonolactone
Central Nervous System
Phenotype
Mutation
Membranes
Enzymes

Keywords

  • Human glioblastoma U-87 MG cells
  • Inflammation
  • Mevalonate kinase deficiency
  • Mevalonolactone
  • Mitochondrial damage
  • Oxidative stress

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

@article{0e75e785fdab4adda4e95373ecb34f9b,
title = "Prolonged treatment with mevalonolactone induces oxidative stress response with reactive oxygen species production, mitochondrial depolarization and inflammation in human glioblastoma U-87 MG cells",
abstract = "Mevalonate pathway impairment has been observed in diverse diseases, including Mevalonate Kinase Deficiency (MKD). MKD is a hereditary auto-inflammatory disorder, due to mutations at mevalonate kinase gene (MVK), encoding mevalonate kinase (MK) enzyme. To date, the most accredited MKD pathogenic hypothesis suggests that the typical MKD phenotypes might be due to a decreased isoprenoid production rather than to the excess and accumulation of mevalonic acid, as initially supported. Nevertheless, recent studies provide clear evidences that accumulating metabolites might be involved in MKD pathophysiology by exerting a toxic effect. Our work aims at describing the effects of accumulating mevalonolactone, mostly produced by a dehydration reaction due to mevalonic acid accumulation, using an in vitro cellular model mimicking the glial component of the central nervous system (human glioblastoma U-87 MG cells). In order to mimic its progressive increase, occurring during the disease, U-87 MG cells have been treated repeatedly with growing doses of mevalonolactone, followed by the assessment of oxidative stress response (evaluated by measuring SOD2 and HemeOX expression levels), ROS production, mitochondrial damage and inflammatory response (evaluated by measuring IL1B expression levels). Our results suggest that protracted treatments with mevalonolactone induce oxidative stress with augmented ROS production and mitochondrial damage accompanied by membrane depolarization. Furthermore, an increment in IL1B expression has been observed, thus correlating the accumulation of the metabolite with the development of a neuroinflammatory response. Our experimental work suggests to reconsider the presence of a possible synergy between the two major MKD pathogenic hypotheses in attempt of unravelling the different pathogenic pathways responsible for the disease.",
keywords = "Human glioblastoma U-87 MG cells, Inflammation, Mevalonate kinase deficiency, Mevalonolactone, Mitochondrial damage, Oxidative stress",
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T1 - Prolonged treatment with mevalonolactone induces oxidative stress response with reactive oxygen species production, mitochondrial depolarization and inflammation in human glioblastoma U-87 MG cells

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AU - Tricarico, Paola Maura

AU - Celsi, Fulvio

AU - Crovella, Sergio

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N2 - Mevalonate pathway impairment has been observed in diverse diseases, including Mevalonate Kinase Deficiency (MKD). MKD is a hereditary auto-inflammatory disorder, due to mutations at mevalonate kinase gene (MVK), encoding mevalonate kinase (MK) enzyme. To date, the most accredited MKD pathogenic hypothesis suggests that the typical MKD phenotypes might be due to a decreased isoprenoid production rather than to the excess and accumulation of mevalonic acid, as initially supported. Nevertheless, recent studies provide clear evidences that accumulating metabolites might be involved in MKD pathophysiology by exerting a toxic effect. Our work aims at describing the effects of accumulating mevalonolactone, mostly produced by a dehydration reaction due to mevalonic acid accumulation, using an in vitro cellular model mimicking the glial component of the central nervous system (human glioblastoma U-87 MG cells). In order to mimic its progressive increase, occurring during the disease, U-87 MG cells have been treated repeatedly with growing doses of mevalonolactone, followed by the assessment of oxidative stress response (evaluated by measuring SOD2 and HemeOX expression levels), ROS production, mitochondrial damage and inflammatory response (evaluated by measuring IL1B expression levels). Our results suggest that protracted treatments with mevalonolactone induce oxidative stress with augmented ROS production and mitochondrial damage accompanied by membrane depolarization. Furthermore, an increment in IL1B expression has been observed, thus correlating the accumulation of the metabolite with the development of a neuroinflammatory response. Our experimental work suggests to reconsider the presence of a possible synergy between the two major MKD pathogenic hypotheses in attempt of unravelling the different pathogenic pathways responsible for the disease.

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