The retrograde response links metabolism with stress responses, chromatin-dependent gene activation, and genome stability in yeast aging

Abstract

Yeast can be used as a model to understand the impact mitochondria have on aging in higher organisms. Mitochondrial dysfunction increases with replicative age in yeast, and this is associated with the induction of the retrograde response. This intracellular signaling pathway from the mitochondrion to the nucleus results in changes in the expression of metabolic and stress genes, which adapt the yeast cell to the loss of tricarboxylic acid cycle activity by providing alternate anaplerotic sources of biosynthetic precursors. The induction of the retrograde response increases longevity. Paradoxically, it also leads to the production of extrachromosomal ribosomal DNA circles, which cause yeast demise. The deleterious effects of these circles are mitigated by the retrograde response, which increases longevity in part due to this effect and partly due to other activities. Rtg2p is the retrograde signal transducer proximal to the mitochondrion, and it interacts with several proteins in relaying the retrograde signal to the transcription factor Rtg1p-Rtg3p. Rtg2p also suppresses ribosomal DNA circle production. When it is engaged in retrograde signaling, it cannot fulfill the latter role. The SAGA-like SLIK complex is one of the protein complexes in which Rtg2p has been found. This histone acetyltransferase, transcriptional co-activator complex contains Gcn5p, and it potentiates the activation of retrograde responsive genes. SLIK complex integrity, and in particular Gcn5p, are needed for retrograde response extension of life span. Thus, the retrograde response through SLIK links metabolism, stress responses, chromatin-dependent gene regulation, and genome stability in yeast aging. Gene regulatory phenomena akin to the retrograde response also operate in human cells, which display both common and cell-type specific changes in gene expression on loss of mitochondrial function.