A network of interorganellar communications underlies cellular aging

Abstract

Organelles within a eukaryotic cell respond to age-related intracellular stresses and environmental factors by altering their functional states to generate, direct and process the flow of interorganellar information that is essential for establishing a pro-or antiaging cellular pattern. The scope of this review is to critically analyze recent progress in understanding how various intercompartmental (i.e., organelle-organelle and organelle-cytosol) communications regulate cellular aging in evolutionarily distant eukaryotes. Our analysis suggests a model for an intricate network of intercompartmental communications that underly cellular aging in eukaryotic organisms across phyla. This proposed model posits that the numerous directed, coordinated and regulated organelle-organelle and organelle-cytosol communications integrated into this network define the long-term viability of a eukaryotic cell and, thus, are critical for regulating cellular aging. V C 2013 IUBMB Life, 65(8):665-674, 2013

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

“…[58][59][60][61][62][63][65][66][67] LCA causes age-related changes in cellular proteome Age-related alterations in the rates and efficiencies of several processes within mitochondria are known to modulate the capacity of these organelles to make and release certain molecular signals; outside mitochondria, such signals have been shown to cause changes in the rates and efficiencies of longevity-defining processes in other cellular locations. [3][4][5][6]16,20,25,31,33,56 Of note, we found that a treatment of yeast cells with LCA alters the agerelated chronology of these mitochondrial processes. 5,36,38,[68][69][70] We therefore hypothesized that LCA may impact not only the levels of numerous mitochondrial proteins but also the levels of proteins in cellular locations outside mitochondria.…”

“…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.…”

“…Noteworthy, the expression of genes encoding mitochondrial proteins that belong to the PMD regulons type 1, 2 and 3 is known to be regulated by the transcription factors Rtg1p/Rtg2p/Rtg3p, Sfp1p and Aft1p. 4,56,57 The expression of genes coding for mitochondrial proteins that belong to the OS regulons type 1, 2 and 3 has been shown to be under the control of the transcription factors Yap1p, Msn2p/Msn4p, Skn7p and Hog1p. [58][59][60][61][62][63][65][66][67] LCA causes age-related changes in cellular proteome Age-related alterations in the rates and efficiencies of several processes within mitochondria are known to modulate the capacity of these organelles to make and release certain molecular signals; outside mitochondria, such signals have been shown to cause changes in the rates and efficiencies of longevity-defining processes in other cellular locations.…”

“…These cellular processes include the following: (1) glycogen degradation; (2) the glycolytic pathway; (3) the pentose phosphate pathway; (4) pyruvate conversion to acetyl-CoA; (5) the maintenance of redox balance between NAD and NADH with the help of carnitine and glycerol-3-phosphate shuttles; (6) ROS detoxification; (7) stress response; (8) glutathione synthesis; (9) gluconeogenesis; (10) ethanol formation; (11) the synthesis and hydrolytic degradation of triacylglycerols (TAG) and ergosteryl esters (EE), the 2 major neutral lipids; (12) the synthesis of various amino acids; (13) nucleotide synthesis; (14) the assembly of the 40S and 60S ribosomal subunits from numerous protein components whose levels were altered by LCA; and (15) proteasomal and vacuolar protein degradation. 4,5,39,41,38,71,72 We then subjected cellular proteins whose levels were changed in yeast grown in a medium supplemented with LCA to bioinformatic analysis with the help of the SPELL online search engine, 51 as described above for mitochondrial proteins. Just as our bioinformatic analysis of mitochondrial proteins revealed (see above), we found that each of the cellular proteins whose level was altered in yeast cultured with LCA belongs to the following 2 multi-clustered regulons: (1) the PMD regulon, which consisted of the rho 0 (Rtg2p governed) cluster, S1 cluster, general TCA cycle dysfunction cluster, kgd1D, kgd2D or lpd1D cluster, yme1Dmdl1D Figure 2.…”

“…[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]…”