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.
Highlights
The mevalonate pathway, crucial for cholesterol synthesis, plays a key role in multiple cellular processes
Regulation begins at the transcriptional level; if cholesterol or other sterol isoprenoids are in shortage, sterol regulatory element binding proteins (SREBP) are activated and they bind to sterol regulatory elements (SREs) present on the HMG-CoA reductase (HMGR) promoter, increasing its transcription [2,3]
By blocking HMG-CoA reductase, statins induce a decrease in cholesterol level and simultaneously other by-products of the mevalonate pathway such as farnesyl pyrophosphate (FPP), geranylgeranyl pyrophosphate (GGPP), dolichols and coenzyme Q10 [12,13]
Summary
The mevalonate pathway, fundamental for cholesterol synthesis, is one of the most important metabolic networks in the cell; it provides essential cell constituents, such as cholesterol, and some of its branches produce key metabolites, such as geranylgeranyl pyrophosphate and farnesyl pyrophosphate, necessary for normal cell metabolism. HMGR is regulated at the post-translational level, by phosphorylation mediated through AMP-activated protein kinase (AMPK) This enzyme is sensitive to the AMP:ATP ratio, and is activated by increased AMP concentration, in casea of metabolic stress, it deactivates HMGR, reducing cellular metabolism [4] (Figure 1a, 2). (MVK) catalyses this conversion, using ATP as a phosphate donor and energy source This enzyme is finely regulated, firstly at transcriptional level in a similar manner of HMGR: SREs are present at the MVK promoter and increases its transcription upon cholesterol shortage [5]. MVK presents feedback inhibition from some of the mevalonate pathway substrates, geranylgeranyl pyrophosphate and farnesyl pyrophosphate, demonstrating that non-sterol isoprenoid could have a key role in regulation of this enzyme [6] (Figure 1a, 3). Cholesterol shortage induces increases in all the three first enzymes of the mevalonate pathway, guaranteeing a continued supply of this key membrane component (Figure 1a, 4)
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