Correlation between the use of statins and COVID-19: what do we know?
Antonio Vitiello, Raffaele La Porta, Francesco Ferrara
Abstract
<h3>ABSTRACT</h3> <h3>Background</h3> Adequate cellular thymidylate (dTMP) pools are essential for preservation of nuclear and mitochondrial genome stability. Previous studies have indicated that disruption in dTMP synthesis in the nucleus leads to increased uracil misincorporation into DNA affecting genome stability. To date, the effects of impaired mitochondrial dTMP synthesis in non- transformed tissues have been understudied. <h3>Objective</h3> This study aimed to determine the effects of decreased serine hydroxymethyltransferase 2 (<i>Shmt2)</i> expression and dietary folate deficiency on mitochondrial DNA integrity and mitochondrial function in mouse tissues. <h3>Methods</h3> Liver mitochondrial DNA (mtDNA) content, and uracil content in liver mtDNA was measured in <i>Shmt2<sup>+/-</sup></i> and <i>Shmt2<sup>+/+</sup></i> mice weaned onto either a folate-sufficient control diet (2 mg/kg folic acid, C) or a modified diet lacking folic acid (0 mg/kg folic acid, FD) for 7 wks. <i>Shmt2<sup>+/-</sup></i> and <i>Shmt2<sup>+/+</sup></i> mouse embryonic fibroblasts (MEF cells) were cultured in defined culture medium containing either 0 or 25 nM folate to assess proliferative capacity and mitochondrial function. <h3>Results</h3> <i>Shmt2<sup>+/-</sup></i> mice exhibited 48-67% reduction in SHMT2 protein levels in tissues. Interestingly, <i>Shmt2<sup>+/-</sup></i> mice consuming the folate-sufficient C diet exhibited a 25% reduction in total folate in liver mitochondria. There was also a >20-fold increase in uracil in liver mtDNA in <i>Shmt2<sup>+/-</sup></i> mice consuming the C diet, and dietary folate deficiency also increased uracil content in mouse liver mtDNA from both <i>Shmt2<sup>+/+</sup></i> and <i>Shmt2<sup>+/-</sup></i> mice. Furthermore, decreased <i>Shmt2</i> expression in MEF cells reduced cell proliferation, mitochondrial membrane potential, and oxygen consumption rate. <h3>Conclusions</h3> This study demonstrates that <i>Shmt2</i> heterozygosity and dietary folate deficiency impair mitochondrial dTMP synthesis, as evidenced by the increased uracil in mtDNA. In addition, <i>Shmt2</i> heterozygosity impairs mitochondrial function in MEF cells. These findings suggest that elevated uracil in mtDNA may impair mitochondrial function.