The mitochondrial ribosomal protein of the large subunit, Afo1p, determines cellular longevity through mitochondrial back-signaling via TOR1

Abstract

Yeast mother cell-specific aging constitutes a model of replicative aging as it occurs in stem cell populations of higher eukaryotes. Here, we present a new long-lived yeast deletion mutation,afo1 (for aging factor one), that confers a 60% increase in replicative lifespan. AFO1/MRPL25 codes for a protein that is contained in the large subunit of the mitochondrial ribosome. Double mutant experiments indicate that the longevity-increasing action of the afo1 mutation is independent of mitochondrial translation, yet involves the cytoplasmic Tor1p as well as the growth-controlling transcription factor Sfp1p. In their final cell cycle, the long-lived mutant cells do show the phenotypes of yeast apoptosis indicating that the longevity of the mutant is not caused by an inability to undergo programmed cell death. Furthermore, the afo1 mutation displays high resistance against oxidants. Despite the respiratory deficiency the mutant has paradoxical increase in growth rate compared to generic petite mutants. A comparison of the single and double mutant strains for afo1 and fob1 shows that the longevity phenotype of afo1 is independent of the formation of ERCs (ribosomal DNA minicircles). AFO1/MRPL25 function establishes a new connection between mitochondria, metabolism and aging.

Lithocholic bile acid accumulated in yeast mitochondria orchestrates a development of an anti-aging cellular pattern by causing age-related changes in cellular proteome

“…The PMD regulon includes the following clusters: (1) rho 0 cluster (which is governed by Rtg2p, a sensor of an age-related reduction of mitochondrial membrane potential); 4,41,52-56 (2) S1 cluster; 4,52,54,55 (3) general TCA cycle dysfunction cluster; 4,52,53,55 (4) kgd1D, kgd2D or lpd1D cluster; 4,53-55 (5) yme1D mdl1D cluster; 4,55 and (6) afo1D cluster (which is governed by Sfp1p, a transcription activator of genes encoding cytoplasmic ribosomal proteins). 4,57 The OS regulon includes the following clusters: (1) a cluster governed by the transcription factor Yap1p, a primary determinant in the antioxidant response of yeast cells; [58][59][60][61][62][63][64] (2) a cluster governed by the transcription factors Msn2p/Msn4p, which are required for expression of numerous genes in response to thermal, oxidative and other types of stress; 56,62-65 (3) a cluster governed by the transcription factor Skn7p, which is involved in the osmotic and oxidative stress responses; [58][59][60][61][62][63][64] and (4) a cluster governed by Hog1p, a mitogen-activated protein kinase orchestrating an osmosensing signal transduction pathway in yeast. 64,66,67 It needs to be emphasized that mitochondrial proteins constituting the PMD and OS regulons exhibit 3 different patterns of the age-related dynamics of changes in their cellular levels; to underscore the existence of such differences in expression, we separated each of the PMD and OS regulons into regulons "type 1", "type 2" and "type 3" (Fig.…”

“…[1][2][3][4][5][6][7] Mitochondria are indispensable for many vital cellular processes, including the following: (1) the synthesis of most cellular ATP via oxidative phosphorylation coupled to the electron transfer chain (ETC) in the inner mitochondrial membrane; 2,3 (2) the generation of the tricarboxylic acid (TCA) cycle intermediates, some of which are used for the synthesis of amino acids, lipids and heme in mitochondria; [3][4][5] (3) the maintenance of a metabolic status-specific NAD C /NADH ratio, AMP/ATP ratio, level of acetyl-CoA and level of S-Adenosylmethionine; these mitochondria-derived metabolites modulate activities of several protein sensors governing energy-producing cellular metabolism and are also used for acetylation and methylation of numerous non-mitochondrial proteins involved in many cellular processes; 3,57,8 (4) the synthesis and assembly of iron-sulfur clusters (ISC), inorganic cofactors of many mitochondrial, nuclear and cytosolic proteins playing essential roles in vital cellular processes; 9 (5) the formation of reactive oxygen species (ROS); these by-products of mitochondrial respiration play critical roles in regulating cell proliferation, differentiation, metabolism, signaling, immune response, aging, survival and death; 4,5,[10][11][12][13][14] (6) the proteolytic degradation of unfolded proteins accumulated in mitochondria above a toxic threshold; the efflux of the resulting peptides from the mitochondria elicits a specific transcriptional response in the nucleus, thus reducing the number of unfolded proteins in mitochondria below the toxic threshold; 4,14-17 (7) the efflux of cytochrome c and other pro-apoptotic proteins from mitochondria to initiate a programmed form of apoptotic cell death as well as to modulate various non-apoptotic cellular processes, including cell cycle progression, differentiation, metabolism, autophagy, inflammation, immunity and regulated necrotic death; [1][2][3]7,[18][19]…”

Regulatory crosstalk of the metabolic network

“…It is therefore advantageous to be able to predict, in advance, the requirements for such changes. Mitochondrial back signalling was recently described as a cascade that monitors respiratory energy production [27]. A decrease in mitochondrial activity, which is indicative of a drop in cellular energy, is used as a signal to inhibit ribosomal biogenesis.…”

“…A yeast strain lacking the mitochondrial ribosomal component Afo1p is deficient for mitochondrial back signalling and respiration, and -as long as fermentable carbon sources are availablegrows normally. Interestingly, this strain is massively long-living and displays an increase of 60% in median replicative lifespan [27].…”

Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice

“…2 Yet this result was not unanticipated. 3 The target of rapamycin (TOR) pathway is involved in senescence of yeast [4][5][6][7] and mammalian cells in culture. [8][9][10][11][12][13][14][15][16] Rapamycin decelerates yeast chronological senescence 5 and suppresses the conversion of cell cycle arrest into senescence in human cells.…”