Rtg2 Protein Links Metabolism and Genome Stability in Yeast Longevity

Abstract

Mitochondrial dysfunction induces a signaling pathway, which culminates in changes in the expression of many nuclear genes. This retrograde response, as it is called, extends yeast replicative life span. It also results in a marked increase in the cellular content of extrachromsomal ribosomal DNA circles (ERCs), which can cause the demise of the cell. We have resolved the conundrum of how these two molecular mechanisms of yeast longevity operate in tandem. About 50% of the life-span extension elicited by the retrograde response involves processes other than those that counteract the deleterious effects of ERCs. Deletion of RTG2, a gene that plays a central role in relaying the retrograde response signal to the nucleus, enhances the generation of ERCs in cells with (grande) or in cells without (petite) fully functional mitochondria, and it curtails the life span of each. In contrast, overexpression of RTG2 diminishes ERC formation in both grandes and petites. The excess Rtg2p did not augment the retrograde response, indicating that it was not engaged in retrograde signaling. FOB1, which is known to be required for ERC formation, and RTG2 were found to be in converging pathways for ERC production. RTG2 did not affect silencing of ribosomal DNA in either grandes or petites, which were similar to each other in the extent of silencing at this locus. Silencing of ribosomal DNA increased with replicative age in either the presence or the absence of Rtg2p, distinguishing silencing and ERC accumulation. Our results indicate that the suppression of ERC production by Rtg2p requires that it not be in the process of transducing the retrograde signal from the mitochondrion. Thus, RTG2 lies at the nexus of cellular metabolism and genome stability, coordinating two pathways that have opposite effects on yeast longevity.

Higher Respiratory Activity Decreases Mitochondrial Reactive Oxygen Release and Increases Life Span in Saccharomyces cerevisiae

“…The deletion of this gene has previously been shown to affect replicative life span (25), bringing further support for the existence of some common pathways in these processes (see Fig. 4).…”

“…CR and SIR2 have been extensively shown to enhance replicative life span by decreasing ERCs, but their effects on chronological life span have not, to our knowledge, been determined to date. Retrograde feedback between nucleus and mitochondria also plays a role in replicative life span by decreasing ERCs, as indicated by the fact that deletion of RTG2, a gene that plays a central role in relaying retrograde response signals, decreases replicative life span (25). However, the effect of RTG2 on chronological life span is also unknown.…”

Cancer as a Metabolic Disease

“…The RTG response would be essential for maintaining a stable ΔG' ATP for cell viability during periods when respiration is impaired. A prolonged RTG response, however, would leave the nuclear genome vulnerable to instability and mutability [112,117,119]. Mitochondrial dysfunction also increases levels of cytoplasmic calcium, the multi-drug resistance phenotype, production of reactive oxygen species, and abnormalities in iron-sulfur complexes, which together would further accelerate aberrant RTG signaling and genome mutability [85,106,107,110,111,[120][121][122].…”

“…As mitochondrial function declines with age, substrate level phosphorylation becomes necessary to compensate for the lost energy from respiration if a cell is to remain alive. A greater reliance on substrate level phosphorylation will induce oncogene expression and unbridled proliferation, which could underlie in part the enhanced longevity in yeast [110,112,119]. When this process occurs in mammalian cells, however, the phenomenon is referred to as neoplasia or "new growth".…”

Copper supplementation increases yeast life span under conditions requiring respiratory metabolism

“…The UTH1 gene is a determinant of yeast longevity and has been linked to mitochondrial biogenesis and degradation (Camougrand et al, 2004). The retrograde response, a signal from mitochondria to the nucleus indicating mitochondrial dysfunction, increases life span when activated Borghouts et al, 2004). Prohibitins, mitochondrial proteins encoded by PHB1 and PHB2, are responsible for proper segregation of mitochondria and, if deleted, cause decreases in life span (Piper et al, 2002;Kirchman et al, 2003).…”