Figure 8. C. elegans retrograde response.

The picture diagrams metabolic changes thought to occur during the yeast retrograde response (Butow and Avadhani 2004). “++” indicates that these same changes are observed in the C. elegans retrograde response. Impairment of electron flow during oxidative phosphorylation is predicted to have two effects. The first is an increase in ROS, due to increased likelihood of electrons transferring to free oxygen (Lenaz 2001). Consistent with increased ROS stress (which we did not assay directly), we observed an increase in cell-protective genes. Secondly, the Krebs cycle is disrupted because the enzyme succinate dehydrogenase is an integral part of both the electron transport chain and of the Krebs cycle. When succinate dehydrogenase oxidizes succinate into fumarate, it feeds electrons into the ETC, and when this flow is blocked, the enzyme's activity is inhibited. The Krebs cycle is necessary for synthesis of glutamate, which in turn is required for amino acid metabolism. Impairment of the electron transport chain leads to decreased glutamate production. Possibly in order to counteract this decrease in glutamate production, the cell induces anaplerotic pathways that feed intermediates into the Krebs cycle, thus allowing production of glutamate. Under conditions of impaired respiration, glycolytic gene expression increases, consistent with glycolysis' becoming a major source of ATP. Consistent with a compensatory response, expression of genes involved in oxidative phosphorylation is up-regulated. OAA, Oxaloacetate; GLU, glutamate; ETC, electron transport chain; α-KG, α-ketoglutarate.