Abstract
Cholesterol metabolism is crucial for cells and, in particular, its biosynthesis in the central nervous system occurs in situ, and its deregulation involves morphological changes that cause functional variations and trigger programmed cell death. The pathogenesis of rare diseases, such as Mevalonate Kinase Deficiency or Smith–Lemli–Opitz Syndrome, arises due to enzymatic defects in the cholesterol metabolic pathways, resulting in a shortage of downstream products. The most severe clinical manifestations of these diseases appear as neurological defects. Expanding the knowledge of this biological mechanism will be useful for identifying potential targets and preventing neuronal damage. Several studies have demonstrated that deregulation of the cholesterol pathway induces mitochondrial dysfunction as the result of respiratory chain damage. We set out to determine whether mitochondrial damage may be prevented by using protective mitochondria-targeted compounds, such as MitoQ, in a neuronal cell line treated with a statin to induce a biochemical block of the cholesterol pathway. Evidence from the literature suggests that mitochondria play a crucial role in the apoptotic mechanism secondary to blocking the cholesterol pathway. Our study shows that MitoQ, administered as a preventive agent, could counteract the cell damage induced by statins in the early stages, but its protective role fades over time.
Highlights
The biosynthesis of cholesterol represents a fundamental pathway for the homeostasis of cells, as witnessed by the heterogeneous spectrum of disorders arising from genetic deficiencies of enzymes involved in this pathway, ranging from inflammatory disorders to complex neurodevelopmental diseases [1,2,3].In general, the pathogenic mechanism of these disorders involves the shortage of compounds downstream of the enzymatic defect, rather than an accumulation of toxic molecules [2,4]. cholesterol is the end stage product of this pathway, several intermediate compounds can contribute to the regulation of crucial cellular functions [1]
Defective synthesis of cholesterol can affect the development of neural cells, and this deficiency may help to explain the occurrence of neurological symptoms in disorders of the cholesterol pathway [2], as Mevalonic Aciduria (MIM#610377) [6] and Smith–Lemli–Opitz Syndrome (MIM#270400) [7]
We demonstrated that blocking the cholesterol pathway in neuronal cells induces dramatic morphological changes to mitochondria, and we hypothesised that mitochondria play a major role in the induction of programmed cell death [8,11]
Summary
The biosynthesis of cholesterol represents a fundamental pathway for the homeostasis of cells, as witnessed by the heterogeneous spectrum of disorders arising from genetic deficiencies of enzymes involved in this pathway, ranging from inflammatory disorders to complex neurodevelopmental diseases [1,2,3]. In order to mimic the blockade of the mevalonate pathway to study its molecular mechanisms at the mitochondrial level, our group developed a biochemical model applicable to several cell lines, including the neuronal one This method identifies statins (lovastatin or simvastatin) as blocking systems of the same metabolic pathway that cause an increase in inflammatory markers [8]. In vivo studies have shown that MitoQ rapidly enters neuronal mitochondria, destroys free radicals, reduces oxidative insults produced by high inflammation, and maintains or even increases neuronal energy in the affected cells In recent years, this product has been considered promising for the treatment of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [13]. The experimental design allowed us to observe the functional and morphological changes induced by biochemical manipulation (Figure 1)
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