RESUMO
Caenorhabditis elegans T09F3.2 is a homolog of the human mitochondrial pyrimidine nucleotide transporter. We isolated a T09F3.2 mutant (TOG2) with a 0.7 kb deletion in T09F3.2, which exhibited low growth and movement. TOG2 worms exhibited high glucose content and low lipid content in intestinal cells and oocytes, suggesting glucose leakage from these cells. The glucose transport inhibitor phloretin improved the growth of TOG2 worms, suggesting that T09F3.2 regulates the phloretin-sensitive glucose transporter FGT-1. The localization of T09F3.2 was examined to assess the regulation of FGT-1 by T09F3.2. Distinct expression of T09F3.2 fused with DsRed-Monomer (T09F3.2:DsRed-Monomer) was observed in the basal domain of intestinal cells and was weakly expressed in many cells. Colocalization of FGT-1 and T09F3.2 was observed in the intestinal cell surface and body wall muscle. This colocalization supports the regulation of FGT-1 by T09F3.2. These results reveal new aspects of glucose transporter regulation.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glucose/metabolismo , Mitocôndrias/metabolismo , Nucleotídeos de Pirimidina/metabolismo , Animais , Transporte Biológico , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/genética , Humanos , Intestinos/fisiologia , Oócitos/metabolismoRESUMO
Aging is an unavoidable process characterized by gradual failure of homeostasis that constitutes a critical risk factor for several age-related disorders. It has been unveiled that manipulation of various key pathways may decelerate the aging progression and the triggering of age-related diseases. As a consequence, the identification of compounds, preferably natural-occurring, administered through diet, with lifespan-extending, anti-aggregation and anti-oxidation properties that in parallel exhibit negligible side-effects is the main goal in the battle against aging. Here we analyze the role of 2,3-dehydrosilybin A/B (DHS A/B), a minor component of silymarin used in a plethora of dietary supplements. This flavonolignan is well-known for its anti-oxidative and neuroprotective properties, among others. We demonstrate that DHS A/B confers oxidative stress resistance not only in human primary cells but also in the context of a multi-cellular aging model, namely Caenorhabditis elegans (C. elegans) where it also promotes lifespan extension. We reveal that these DHS A/B outcomes are FGT-1 and DAF-16 dependent. We additionally demonstrate the anti-aggregation properties of DHS A/B in human cells of nervous origin but also in nematode models of Alzheimer's disease (AD), eventually leading to decelerated progression of AD phenotype. Our results identify DHS A/B as the active component of silymarin extract and propose DHS A/B as a candidate anti-aging and anti-aggregation compound.