Caenorhabditis elegans: A useful model for studying metabolic disorders in which oxidative stress is a contributing factor

Abstract

Caenorhabditis elegans is a powerful model organism that is invaluable for experimental research because it can be used to recapitulate most human diseases at either the metabolic or genomic level in vivo. This organism contains many key components related to metabolic and oxidative stress networks that could conceivably allow us to increase and integrate information to understand the causes and mechanisms of complex diseases. Oxidative stress is an etiological factor that influences numerous human diseases, including diabetes. C. elegans displays remarkably similar molecular bases and cellular pathways to those of mammals. Defects in the insulin/insulin-like growth factor-1 signaling pathway or increased ROS levels induce the conserved phase II detoxification response via the SKN-1 pathway to fight against oxidative stress. However, it is noteworthy that, aside from the detrimental effects of ROS, they have been proposed as second messengers that trigger the mitohormetic response to attenuate the adverse effects of oxidative stress. Herein, we briefly describe the importance of C. elegans as an experimental model system for studying metabolic disorders related to oxidative stress and the molecular mechanisms that underlie their pathophysiology.

Figure 1

Machinery that protects against oxidative stress and intracellular ROS overproduction. The principal ROS include the superoxide anion (O₂ ^•−), hydrogen peroxide (H₂O₂), and the hydroxyl radical (HO^•). Cellular redox homeostasis is maintained by a set of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and peroxiredoxin (Prx).

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.