title: Mevalonate Pathway Blockade, Mitochondrial Dysfunction and Autophagy: A Possible Link.
abstract: The mevalonate pathway, crucial for cholesterol synthesis, plays a key role in multiple cellular processes. Deregulation of this pathway is also correlated with diminished protein prenylation, an important post-translational modification necessary to localize certain proteins, such as small GTPases, to membranes. Mevalonate pathway blockade has been linked to mitochondrial dysfunction: especially involving lower mitochondrial membrane potential and increased release of pro-apoptotic factors in cytosol. Furthermore a severe reduction of protein prenylation has also been associated with defective autophagy, possibly causing inflammasome activation and subsequent cell death. So, it is tempting to hypothesize a mechanism in which defective autophagy fails to remove damaged mitochondria, resulting in increased cell death. This mechanism could play a significant role in Mevalonate Kinase Deficiency, an autoinflammatory disease characterized by a defect in Mevalonate Kinase, a key enzyme of the mevalonate pathway. Patients carrying mutations in the MVK gene, encoding this enzyme, show increased inflammation and lower protein prenylation levels. This review aims at analysing the correlation between mevalonate pathway defects, mitochondrial dysfunction and defective autophagy, as well as inflammation, using Mevalonate Kinase Deficiency as a model to clarify the current pathogenetic hypothesis as the basis of the disease.
authors.affiliation: Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, 34128 Trieste, Italy. paola.tricarico@burlo.trieste.it.
authors.forename: Paola Maura
authors.initials: PM
authors.lastname: Tricarico
authors.affiliation: Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, 34128 Trieste, Italy. fulvio.celsi@gmail.com.|Institute for Maternal and Child Health "Burlo Garofolo", via dell'Istria 65/1, 34137 Trieste, Italy. fulvio.celsi@gmail.com.
authors.forename: Sergio
authors.initials: S
authors.lastname: Crovella
authors.affiliation: Institute for Maternal and Child Health "Burlo Garofolo", via dell'Istria 65/1, 34137 Trieste, Italy. fulvio.celsi@gmail.com.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Celsi
mesh_terms: D001343:Autophagy / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D054078:Mevalonate Kinase Deficiency / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008798:Mevalonic Acid / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D017368:Protein Prenylation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D058570:TOR Serine-Threonine Kinases; D008798:Mevalonic Acid
keywords: Mevalonate Kinase Deficiency; autophagy; inflammation; mevalonate pathway; mitochondrial dysfunction; statins