The retrograde response: a conserved compensatory reaction to damage from within and from without

The retrograde response was discovered in Saccharomyces cerevisiae as a signaling pathway from the mitochondrion to the nucleus that triggers an array of gene regulatory changes in the latter. The activation of the retrograde response compensates for the deficits associated with aging, and thus it extends yeast replicative life span. The retrograde response is activated by the progressive decline in mitochondrial membrane potential during aging that is the result of increasing mitochondrial dysfunction. The ensuing metabolic adaptations and stress resistance can only delay the inevitable demise of the yeast cell. The retrograde response is embedded in a network of signal transduction pathways that impinge upon virtually every aspect of cell physiology. Thus, its manifestations are complicated. Many of these pathways have been implicated in life span regulation quite independently of the retrograde response. Together, they operate in a delicate balance in promoting longevity. The retrograde response is closely aligned with cell quality control, often performing when quality control is not sufficient to assure longevity. Among the key pathways related to this aspect of retrograde signaling are target of rapamycin and ceramide signaling. The retrograde response can also be found in other organisms, including Caenorhabditis elegans, Drosophila melanogaster, mouse, and human, where it exhibits an ever-increasing complexity that may be corralled by the transcription factor NFκB. The retrograde response may have evolved as a cytoprotective mechanism that senses and defends the organism from pathogens and environmental toxins.