Block of the mevalonate pathway triggers oxidative and inflammatory molecular mechanisms modulated by exogenous isoprenoid compounds.
Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines' release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD.
Department of Medicine and Surgery and Health, University of Trieste, Piazzale Europa, 1, 34128 Trieste, Italy. tricaricopa@gmail.com.
Paola Maura
PM
Tricarico
Institute for Maternal and Child Health IRCCS "Burlo Garofolo", 34137 Trieste, Italy. giulio.kleiner@burlo.trieste.it.
Giulio
G
Kleiner
Institute for Maternal and Child Health IRCCS "Burlo Garofolo", 34137 Trieste, Italy. erica.valencic@gmail.com.
Erica
E
Valencic
Department of Medicine and Surgery and Health, University of Trieste, Piazzale Europa, 1, 34128 Trieste, Italy. g.campisciano@gmail.com.
Giuseppina
G
Campisciano
Institute for Maternal and Child Health IRCCS "Burlo Garofolo", 34137 Trieste, Italy. martina.girardelli@burlo.trieste.it.
Martina
M
Girardelli
Department of Medicine and Surgery and Health, University of Trieste, Piazzale Europa, 1, 34128 Trieste, Italy. sergio.crovella@burlo.trieste.it.
Sergio
S
Crovella
Institute for Maternal and Child Health IRCCS "Burlo Garofolo", 34137 Trieste, Italy. alessandra.knowles@burlo.trieste.it.
Alessandra
A
Knowles
Institute for Maternal and Child Health IRCCS "Burlo Garofolo", 34137 Trieste, Italy. annalisa.marcuzzi@burlo.trieste.it.
Annalisa
A
Marcuzzi
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002338:Carotenoids / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D006801:Humans; D000077276:Lycopene; D054078:Mevalonate Kinase Deficiency / Q000378:metabolism / Q000473:pathology; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009569:Nitric Oxide / Q000378:metabolism; D010836:Phytol / Q000494:pharmacology; D013729:Terpenes / Q000633:toxicity
D002352:Carrier Proteins; D016207:Cytokines; D004224:Diterpenes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D013729:Terpenes; D010836:Phytol; D009569:Nitric Oxide; D002338:Carotenoids; C017338:geranylgeraniol; D008798:Mevalonic Acid; D000077276:Lycopene