Yeast cells share most of the interesting mechanisms relevant to aging with mammalian cells, but are very cheap to work with in comparison to mammals, which is why a lot of fundamental research starts with yeast. In the paper linked below, scientists use yeast to investigate the way in which cellular maintenance mechanisms in different parts of the cell react to one another's circumstances. This is of interest because the maintenance processes that remove damaged or waste proteins, as well as structures within the cell, are important determinants in the natural aging process. Many of the methods of somewhat slowing aging demonstrated in animal studies involve increased maintenance activities. This is also the basis for hormetic effects, in which exposure to a little damage can produce a net benefit because it provokes a larger and lengthy increase in cellular maintenance.
The intriguing portion of the results is this: because of the cross-talk between repair mechanisms in different parts of the cell, the researchers can make yeast cells live longer by very selectively disabling functions of cell maintenance in just one portion of the cell. The disabled portion might be broken, but maintenance activities in other parts of the cell pick up the slack, and the result is an extended functional lifetime for that cell.
Cells have acquired multiple mechanisms for the maintenance of protein structure and function. This implies an activity that would enable thousands of cellular proteins to fold, correctly and efficiently, under both optimal and challenging conditions. Molecular chaperones, including the heat-shock proteins (Hsps), are ubiquitously present cellular proteins, which display a wide spectrum of folding-oriented activities, coping with regular protein folding events as well as stress-induced protein misfolding. Naturally, such protein homeostasis (proteostasis) may decline in performance, as seen in numerous diseases and aging.
In compartmentalized eukaryotic cells, several independent pathways exist that ensure the integrity of the protein-folding environments in the cytosol, the endoplasmic reticulum (ER), and the mitochondria. The current knowledge posits that misfolded protein stress is sensed in a compartment-specific manner to induce the expression of compartment-specific chaperones. However, in this study we addressed the persisting question of cell-wide consequences of proteostasis failure in specific cellular compartments. We monitored the effect of loss-of-function of cytosolic, mitochondrial, and ER chaperones, each involved in protein input into different organelles, as well as protein folding. Our results show that the loss of each studied chaperone, regardless of the compartment of its residence and activity, induces a common cross-organelle response (CORE) that includes protein maintenance and antioxidant responses in the cytosol, mitochondria and the ER, without activating any of the canonical stress response pathways.
In order to induce protein stress in several different cellular compartments, we independently deleted a gene copy of three protein chaperones: cytosolic nascent polypeptide associated complex (NAC, EGD2), HSP70 chaperone from the endoplasmic reticulum (erHSP70, LHS1), and mitochondrial HSP70 (mtHSP70, SSC1). We set out to measure the replicative lifespan (RLS) of the studied chaperone deficient mutants. RLS is measured as the maximum number of generations that each mother cell goes through before the onset of senescence. The control strain produced a maximum of 19 buds during its RLS, which corresponds to the expected value for this strain. The largest effect on RLS with a 40% lifespan extension, in comparison to the control, resulted from the deletions of EGD2, encoding a subunit of the nascent polypeptide associated complex (NAC), as well as SSC1, mtHSP70. Finally, the deletion of LHS1, erHsp70, resulted in 30% lifespan extension relative to the control. Furthermore, we monitored the chronological lifespan (CLS) of the studied strains, measured as the mean and maximum survival time of non-dividing yeast populations. As with the replicative lifespan, we found that the chronological lifespan was extended in all chaperone deficient mutants, with the largest effect in the deletion of LHS1 (app 40%), followed by the deletion of EGD2 with 25% extension. As in the case of RLS, the smallest effect was observed in the deletion of the SSC1, with only 15% extension.
It is a feature of CORE that, regardless of the compartment in which the chaperone is deficient, the stress response seems to be cell-wide and unique in all studied strains. The response consists of changes in two groups of genes: (i) cellular maintenance, and (ii) metabolic changes, including a decline in respiration. The questions persist how the information on the folding environment status is communicated between the organelles and why none of the canonical stress responses have been activated by the deficiency of the three studied chaperones. At this point, we can only speculate that due to redundancy with other chaperones in each compartment, the cell perceives the absence of each of the three chaperones as mild proteotoxic stress. Therefore, specific signals needed to activate some of the canonical stress response pathways are likely to be missing during CORE, while the nature of signals generated to communicate the status of folding environment between cellular organelles will be a subject of further research.