Current Research Projects



Citrate pathway in inflammation

Citrate is a key intermediate metabolite. After its synthesis in mitochondria, citrate can be transported into the cytosol by the citrate carrier (CIC), a member of the mitochondrial carrier family encoded by the SLC25A1 gene. In the cytosol, citrate is cleaved by ATP-citrate lyase (ACLY) to acetyl-CoA, which is the precursor for fatty acid and sterol biosynthesis and the universal donor for acetylation reactions. A second metabolic product generated from the cleavage of citrate is oxaloacetate (OAA), which is reduced to malate by cytosolic malate dehydrogenase and converted to pyruvate via malic enzyme in a reaction that generates cytosolic NADPH plus H+. We refer to CIC plus ACLY as “citrate pathway”. Recently, we have found that lipopolysaccharides as well as TNFα and INFγ cytokines activate both SLC25A1 and ACLY genes in immune cells. Moreover, CIC and ACLY activities are required for inflammatory response in macrophages. This function of the citrate pathway in pro-inflammatory signaling provides new insights on the relationship between energy metabolism and inflammation. Our goal is to deepen understanding of the citrate pathway role in chronic inflammatory diseases and in the wider context of immunometabolism.


Liver cell biology in physiological and pathological processes

The liver is the metabolic center of the mammalian body by regulating complex biochemical functions such as nutrient homeostasis (proteins, carbohydrates and lipids) and xenobiotic detoxification. Dysregulation of nutrient metabolism is a key step during the progression of chronic liver disease inducing an inflammatory status, cell damage, and impaired hepatic insulin signaling, which leads to insulin resistance. Mitochondrial functions - such as lipid metabolism and TCA cycle - are essential for hepatic metabolic activities and detoxification. We are investigating molecular mechanisms underlying gene expression of mitochondrial proteins in different conditions. Our goal is to evaluate the biological effect of new PPARa ligands in order to identify effective and safe lipid-lowering agents for hypercholesterolemia and dyslipidemia. Moreover, we are studying gene expression changes in hepatocellular carcinoma (HCC) and compounds selectively cytotoxic to liver tumor cells.


Mitochondrial function and immunometabolism in Down Syndrome

Down's syndrome (DS) is the most common autosomal trisomy among live births. It is caused by trisomy of either the entire or critical portions of human chromosome 21. Although the perception of DS as a metabolic disease is not prevalent, overexpression of genes encoding specific enzymes directly leads to biochemical aberrations that affect multiple interacting metabolic pathways, culminate in cellular dysfunction and contribute to the pathogenesis of DS. Indeed we have recently reported that impairment of cellular methyl cycle in DS subjects - probably due to the location of CBS and other methyl cycle genes on chromosome 21 - limits cellular availability of SAM and its mitochondrial uptake reducing methylation in DS mitochondria compared to controls. It is also known that inflammatory condition and oxidative stress have a crucial role in DS. Now, we are interested in the relationship between inflammatory signaling and energetic metabolism in DS children.