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Int. J. Mol. Sci. 2015, 16(7), 16067-16084; doi:10.3390/ijms160716067

Mevalonate Pathway Blockade, Mitochondrial Dysfunction and Autophagy: A Possible Link

1
Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, 34128 Trieste, Italy
2
Institute for Maternal and Child Health "Burlo Garofolo", via dell'Istria 65/1, 34137 Trieste, Italy
*
Author to whom correspondence should be addressed.
Academic Editors: Lars Olson, Jaime M. Ross and Giuseppe Coppotelli
Received: 5 May 2015 / Revised: 6 July 2015 / Accepted: 9 July 2015 / Published: 15 July 2015
(This article belongs to the Special Issue Mitochondrial Dysfunction in Ageing and Diseases)
View Full-Text   |   Download PDF [1487 KB, uploaded 15 July 2015]   |  

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. View Full-Text
Keywords: autophagy; mevalonate pathway; mitochondrial dysfunction; inflammation; Mevalonate Kinase Deficiency; statins autophagy; mevalonate pathway; mitochondrial dysfunction; inflammation; Mevalonate Kinase Deficiency; statins
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Tricarico, P.M.; Crovella, S.; Celsi, F. Mevalonate Pathway Blockade, Mitochondrial Dysfunction and Autophagy: A Possible Link. Int. J. Mol. Sci. 2015, 16, 16067-16084.

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