The significance of peroxisome function in chronological aging ofSaccharomyces cerevisiae

Abstract

We studied the chronological lifespan of glucose-grown Saccharomyces cerevisiae in relation to the function of intact peroxisomes. We analyzed four different peroxisome-deficient (pex) phenotypes. These included Δpex3 cells that lack peroxisomal membranes and in which all peroxisomal proteins are mislocalized together with Δpex6 in which all matrix proteins are mislocalized to the cytosol, whereas membrane proteins are still correctly sorted to peroxisomal ghosts. In addition, we analyzed two mutants in which the peroxisomal location of the β-oxidation machinery is in part disturbed. We analyzed Δpex7 cells that contain virtually normal peroxisomes, except that all matrix proteins that contain a peroxisomal targeting signal type 2 (PTS2, also including thiolase), are mislocalized to the cytosol. In Δpex5 cells, peroxisomes only contain matrix proteins with a PTS2 in conjunction with all proteins containing a peroxisomal targeting signal type 1 (PTS1, including all β-oxidation enzymes except thiolase) are mislocalized to the cytosol. We show that intact peroxisomes are an important factor in yeast chronological aging because all pex mutants showed a reduced chronological lifespan. The strongest reduction was observed in Δpex5 cells. Our data indicate that this is related to the complete inactivation of the peroxisomal β-oxidation pathway in these cells due to the mislocalization of thiolase. Our studies suggest that during chronological aging, peroxisomal β-oxidation contributes to energy generation by the oxidation of fatty acids that are released by degradation of storage materials and recycled cellular components during carbon starvation conditions.

Artemisinin mimics calorie restriction to extend yeast lifespan via a dual-phase mode: a conclusion drawn from global transcriptome profiling

“…Therefore, it seems that MAPK may not be activated due to ROS deprival although the correlation of ROS levels with MAPK activity and MAPK gene expression is yet to be identified in yeast. On the other hand, it is accepted that protein kinases are implicated in yeast longevity [19,29,39,40], we actually observed the significant upregulation of Tor1 in PME yeast cells, which is as same as the case described in fission yeast [41]. It is unclear, however, whether the upregulation of Tor1 is due to the inhibition of Tor1p per se upon exposure of yeast cells to CR, ART, or H 2 O 2 .…”

“…Besides, we also observed the upregulation of peroxisomal β-oxidation genes responsible for the oxidation of long-chain fatty acids. A most recently published report has indicated CR-activated peroxisomal β-oxidation systems during yeast CLS contribute to energy regeneration by stored lipids and recycled cellular components [29].…”

Cell-autonomous mechanisms of chronological aging in the yeast Saccharomyces cerevisiae

“…Among them are the following "downstream" processes (Figure 2): (1) the maintenance of trehalose homeostasis, a longevity-defining process known to modulate proteostasis in chronologically "young" and "old" cells 2361 (Figure 1A); (2) the maintenance of the homeostasis of glycogen, a reserve carbohydrate whose elevated level in chronologically "young" and "old" cells is a hallmark of carbohydrate metabolism remodeling in yeast cultured under CR 23; (3) the maintenance of the homeostasis of neutral lipids deposited within LD, a process known to play an essential role in regulating longevity of chronologically aging yeast 142392 (Figure 1B); (4) peroxisomal oxidation of fatty acids, a process implicated in yeast chronological aging 14239192 (Figure 1B); (5) the maintenance of the homeostasis of non-esterified ("free") fatty acids and diacylglycerol, whose reduced levels in chronologically "young" and "old" cells are characteristic of lipid metabolism remodeling in yeast cultured under CR - a pattern likely linked to the demonstrated abilities of both lipid species to elicit an age-related form of liponecrotic PCD 1423103 (Figure 1B); (6) the maintenance of a balance between the relative rates of glycolysis and gluconeogenesis, a process known to impact the level of ethanol in chronologically "young" and "old" yeast - thus defining the extent to which this product of glucose fermentation suppresses the longevity-extending process of peroxisomal oxidation of fatty acids 1423 (Figure 1B); (7) the longevity-extending process of mitochondrial translation 23505156; (8) the maintenance of a balance between the relative rates of mitochondrial fusion and fission, a process known to define the size and number of mitochondria, the length of mitochondrial cristae extending from the IMM, and the level of ATP synthesized in mitochondria of chronologically "young" and "old" yeast 14236470; (9) the development of an age-related pattern of susceptibility to chronic oxidative, thermal and osmotic stresses 314233350565962; (10) an age-related form of apoptotic PCD, which in chronologically "young" yeast is manifested in such early hallmark events of this PCD as the fragmentation of a tubular mitochondrial network into individual mitochondria, release of cytochrome c from mitochondria into the cytosol and phosphatidylserine (PS) translocation from the inner to the outer leaflet of the plasma membrane 1423 (Figure 1B); and (11) the development of a pattern of cell susceptibility to an age-related forms of apoptotic and liponecrotic PCD elicited by an exposure to exogenous hydrogen peroxide or palmitoleic acid, respectively 142359103.…”

Quantitative Analysis of Proteome and Lipidome Dynamics Reveals Functional Regulation of Global Lipid Metabolism

“…To assess which physiological processes are modulated, we sorted proteins based on gene ontology (GO) categories for cellular components and biochemical pathway annotation, and determined the mean fold change within each structural or functional category (Figure 3; File S1). Changes related to cellular components (Figures 3A-3C) show (i) increased levels of mitochondrial proteins consistent with the increase of mitochondrial content when cells are transferred from a fermentable to a non-fermentable carbon source (Egner et al, 2002); (ii) an increase in levels of peroxisomal proteins consistent with peroxisome proliferation in the Table S1. post-diauxic phase (Lefevre et al, 2013); and (iii) a decrease in nucleolar and ribosomal proteins showing a down-regulation of protein synthesis, with the exception of mitochondrial ribosomal proteins which are up-regulated in the post-diauxic phase ( Figure 3B). Assessing co-regulated biochemical pathways ( Figures 3D and 3E) confirms the aforementioned induction of ethanol degradation, the TCA cycle, the glyoxylate cycle, and gluconeogenesis, and uncovered other processes activated in the post-diauxic phase including (i) the oxidation of fatty acids, (ii) the related carnitine shuttle and removal of superoxide radicals, (iii) the degradation of glycerol, and (iv) the synthesis of the lipid precursor inositol.…”