The Relationship Between ERCs and Protein Aggregates In the Context of Replicative Aging in Saccharomyces cerevisiae

Abstract

Aging is a universal phenomenon that is even observed in inorganic material. In the inorganic world it is associated with damage induced weariness, yet in the organic world it presents a much more complicated and interesting case. In biology, aging is defined as the time-dependent decline in vital functions of an organism. This was inherently associated with damage accumulation over time. However, mounting evidence from recent years have provided data that are a suggestive of an alternative view. They have shown that aging might be coupled with differentiation and non-mendelian trait acquisitions (memory). Therefore, the nature of an aging factor has become more interesting over the years. Using the unicellular eukaryote Saccharomyces cerevisiae I have asked myself a simple question: What causes aging? Two types of molecules have been associated with aging in the last years: extra-chromosomal rDNA circles (ERCs) and protein aggregates. Nevertheless, it is still unknown if the behavior of one affects the other, or if one’s effect can be exclusively influential of the other. I asked if age-dependent protein aggregation and ERCs worked together or seperately. By using mutants that decrease age-dependent protein aggregation (APOD), I have observed that ERC retention is significantly altered. My results indicate that when cells fail to collect protein aggregates into one location with the help of HSP40 family chaperone Hsp42, a pathway including mitochondrial signaling is activated and the formation of the nuclear diffusion barrier is suppressed. Consequently fewer DNA-circle-attached NPCs are retained in the mother nucleus. This leads to the sharing of aging factors such as ERCs with the progeny. Additionally, a similar effect on DNA-circle segregation can be induced by changing the external nitrogen-source of the cells. My results suggest that APOD formation serves a protective role for the progeny. Furthermore, these data indicate that mitochondria are involved in sensing cytoplasmic stress and nuclear compartmentalization during mitosis. I conclude by proposing that the aging phenotypes seen in mutants with decreased protein aggregation is actually caused by effects that include ERCs. I also show that protein aggregation is part of heat-induced ethanol tolerance, and regulated by protein chaperons. Together with these results I end with a proposal that cellular aging actually is not irreversible damage accumulation, but rather an adaptation fatigue experienced by cells.