Caenorhabditis elegans: A Useful Model for Studying Metabolic Disorders in Which Oxidative Stress Is a Contributing Factor
Figure 2
Cross-talk between mitochondrial metabolism and the IIS pathway is required to trigger the mitohormetic response in C. elegans. The C. elegans IIS pathway contains components that are nearly identical to those of mammals [87]; under conditions of nutrient supply, the IIS pathway is initiated by the binding of DAF-28 or INS-7 [88, 89] to DAF-2 [12, 90], subsequently triggering a cascade of phosphorylation events to activate specific kinases that inactivate the transcriptional factor DAF-16 and its target genes (e.g., sod-3) [86, 91]. A similar mechanism occurs for the transcriptional factor SKN-1 via the kinases AKT-1/2 and SGK-1. Conversely, the transcriptional activity of SKN-1 is augmented by some stressors, such as oxidative stress, as a consequence of OXPHOS activity via PMK-1 kinase, culminating in the nuclear translocation of SKN-1 and its interaction with the DNA-binding sites (AREs) of its target genes (gst-10, gcs-1, and sod-1). Finally, an antioxidant response is activated to prevent ROS-mediated cellular damage, which may support the mitohormetic theory. DAF-28 and INS-7, insulin-like peptides; DAF-2, insulin/IGF-1 receptor; IST-1, insulin receptor substrate 1 ortholog; AGE-1 and AAP-1, phosphatidylinositol 3-kinases; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3); PDK-1, 3-phosphoinositide-dependent kinase 1; DAF-18, homologous to human PTEN; AKT1/2 and SGK-1, orthologs of the serine/threonine kinase Akt/PKB; DAF-16, FOXO transcription factor; SKN-1, skinhead family member 1, the ortholog of mammalian Nrf-2; PMK-1, the p38 MAPK ortholog; WDR-23, possible functional homolog of Keap1; DDB-1/CUL-4, ubiquitin ligase complex; ARE, antioxidant response element; OXPHOS, oxidative phosphorylation; GST-10/gst-10, glutathione S-transferase-10; GCS-1/gcs-1, γ-glutamyl cysteine synthetase-1; and SOD-1/sod-1 and SOD-3/sod-3, superoxide dismutase-1 and -3, respectively.
