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Review
. 2015 Mar 11;16(3):5528-54.
doi: 10.3390/ijms16035528.

Mechanisms by Which Different Functional States of Mitochondria Define Yeast Longevity

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Free PMC article
Review

Mechanisms by Which Different Functional States of Mitochondria Define Yeast Longevity

Adam Beach et al. Int J Mol Sci. .
Free PMC article

Abstract

Mitochondrial functionality is vital to organismal physiology. A body of evidence supports the notion that an age-related progressive decline in mitochondrial function is a hallmark of cellular and organismal aging in evolutionarily distant eukaryotes. Studies of the baker's yeast Saccharomyces cerevisiae, a unicellular eukaryote, have led to discoveries of genes, signaling pathways and chemical compounds that modulate longevity-defining cellular processes in eukaryotic organisms across phyla. These studies have provided deep insights into mechanistic links that exist between different traits of mitochondrial functionality and cellular aging. The molecular mechanisms underlying the essential role of mitochondria as signaling organelles in yeast aging have begun to emerge. In this review, we discuss recent progress in understanding mechanisms by which different functional states of mitochondria define yeast longevity, outline the most important unanswered questions and suggest directions for future research.

Figures

Figure 1
Figure 1
Seven strategies allow mitochondria to operate as intracellular signaling compartments and organizing platforms that orchestrate cellular responses to changes in physiological conditions. Strategy 1: mitochondria can change NAD+/NADH, AMP/ATP and acetyl-CoA/CoA ratios inside and outside of mitochondria, thus enabling these key metabolites to modulate activities of several protein sensors. These sensors then alter cellular energy status by amending activities of proteins involved in various metabolic pathways; Strategy 2: mitochondria can generate and release reactive oxygen species (ROS). If the concentration of ROS released from mitochondria surpasses a toxic threshold, ROS cause health-demoting oxidative damage to cellular macromolecules. In contrast, if it is maintained at a sub-lethal (hormetic) level, ROS modulate activities of several protein sensors, which then alter activities of many protein targets to accelerate health-promoting cellular processes; Strategy 3: mitochondria can synthesize and assemble iron-sulfur clusters (ISC). ISC are essential cofactors of numerous proteins located inside and outside of mitochondria; these proteins are involved in many cellular processes; Strategy 4: mitochondria can release peptides, proteins, mitochondrial DNA (mtDNA) and mtDNA fragments. These mitochondria-derived signaling macromolecules act in a cell-autonomous and cell-non-autonomous manner to elicit changes in vital processes that take place in the “host” cells and within the distal cells in other tissues; Strategy 5: mitochondrial surface can serve as an organizing platform for assembly and disassembly of multi-protein complexes implicated in a number of essential processes; Strategy 6: mitochondria can form zones of close apposition to the mitochondria-associated membrane (MAM) domains of other organellar and cellular membranes. These MAM domains are known for their essential roles in many cellular processes; Strategy 7: mitochondria can form small vesicles. These vesicles deliver certain proteins and lipids to lysosomes and peroxisomes, thereby enabling mitochondrial quality control and playing a role in peroxisome biogenesis and function. See the text for additional details.
Figure 2
Figure 2
Mechanisms underlying the essential role of mitochondria in yeast replicative aging. (A) A decline in the mitochondrial electron transport chain (ETC) and the resulting reduction of mitochondrial membrane potential (ΔΨ) delay replicative aging in yeast by: (1) stimulating Rtg2-dependent nuclear import of the Rtg1-Rtg3 heterodimeric transcription factor, thereby activating the mitochondrial retrograde signaling pathway; (2) promoting the import of Rtg2 into the nucleus, where it increases genome stability; and (3) reducing a protein kinase activity of the target of rapamycin protein 1 (Tor1). The reduction of ΔΨ also attenuates mitochondrial synthesis and/or export of iron-sulfur clusters (ISC), which are needed for maintaining genome stability and inhibiting the Aft1-driven transcription of nuclear genes involved in iron entry into the cell; (B) A transition from the early-age stage to the intermediate-age stage of replicative aging coincides with a rise of mitochondrial reactive oxygen species (ROS) and fragmentation of mitochondria in the mother cell; these fragmented mitochondria produce more ROS, aggregate and lose mitochondrial DNA (mtDNA) during the subsequent late-age stage of replicative aging. The dysfunctional mitochondria formed during the intermediate-age and late-age stages of replicative aging are so-called “aging factors”. They limit the replicative lifespan of the mother cell; their Sir2- and Myo2-driven movement to the daughter cell occurs slower than that of fully functional mitochondria; (C) A reduction in the quantity of the Afo1 protein component of the large subunit of the mitochondrial ribosome delays replicative aging in yeast by: (1) stimulating Sfp1-driven transcription of nuclear genes encoding protein components of cytoplasmic ribosomes; and (2) attenuating the TOR signaling pathway, which accelerates the pro-aging process of protein synthesis in the cytosol and also slows down the anti-aging processes of autophagy and transcription of stress-response genes in the nucleus; (D) Mitochondrial translation control (MTC) proteins assist in processing, stabilization and translation of mRNAs encoded by mtDNA. A reduction in the quantity of MTC proteins slows down replicative aging in yeast by: (1) triggering the Pnc1- and Sir2-dependent inhibition of the synthesis of extrachromosomal rDNA circles; and (2) reducing the cellular concentration of cAMP and thus attenuating the cAMP-dependent protein kinase A (PKA) activity, which decelerates the anti-aging processes of autophagy and transcription of stress-response genes in the nucleus and also accelerates the pro-aging process of protein synthesis in the cytosol; (E) Afg3 is a mitochondrial protease involved in maintaining protein homeostasis (proteostasis) in mitochondria. The Afg3-driven processes in mitochondria include degradation of misfolded proteins, assembly of ETC protein complexes and processing of a protein component of the large subunit of the mitochondrial ribosome; these proteostatic processes within mitochondria stimulate such pro-aging processes outside of these organelles as protein synthesis in the cytosol and the accumulation of unfolded proteins in the endoplasmic reticulum (ER); (F) The Uth1 protein in the mitochondrial outer membrane is a pro-aging factor that accelerates replicative aging in yeast by concurrently weakening macromitophagic degradation of dysfunctional mitochondria and enhancing micromitophagic degradation of functional mitochondria. Activation arrows and inhibition bars denote pro-aging processes (displayed in blue color) or anti-aging processes (displayed in red color). See the text for additional details.
Figure 3
Figure 3
A chronologically aging culture of yeast cells progresses through at least seven consecutive “checkpoints”, each of which defines yeast longevity. Checkpoint 1: The protein kinase Tor1 mitigates the synthesis of mitochondrial DNA-encoded enzymes of the oxidative phosphorylation (OXPHOS) system in mitochondria, thereby allowing to set up a certain rate of electron flow through the mitochondrial electron transport chain (ETC) and a certain value of mitochondrial membrane potential (ΔΨ). These two traits of mitochondrial functionality establish a magnitude of cell resistance to stresses and, thus, define the chronological lifespan of yeast. Caloric restriction extends yeast chronological lifespan by suppressing Tor1; Checkpoint 2: Mitochondria-generated NADPH is an electron donor for thioredoxin and glutathione reductase (TRR and GLR, respectively) systems outside of mitochondria. Both these systems delay yeast chronological aging by reducing the degree of oxidative damage to many proteins in various cellular locations; Checkpoint 3: The efficiency of coupled mitochondrial respiration defines the cellular concentration of trehalose, which in chronologically “young” yeast cells acts as a longevity-extending metabolite by enhancing cellular proteostasis; Checkpoint 4: If mitochondria-generated reactive oxygen species (ROS) in chronologically “young” yeast cells are maintained at a “hormetic” level, ROS extend chronological lifespan by: (1) activating the transcription factors Gis1, Msn2 and Msn4, which promote expression of many longevity-extending nuclear genes; and (2) stimulating the longevity-extending Tel1-Rad53-Rph1 signaling pathway, which reduces the extent of damage to telomeric DNA in the nucleus; Checkpoint 5: Amino acids that are synthesized in and released from mitochondria activate the TOR signaling pathway; this pathway accelerates chronological aging by simulating protein synthesis in the cytosol, attenuating transcription of many stress-response genes in the nucleus, and suppressing autophagy of dysfunctional organelles and macromolecules; Checkpoint 6: A release of cytochrome c, Aif1 and Nuc1 from fragmented mitochondria in chronologically “old” yeast cells stimulates caspase-dependent and caspase-independent modes of apoptotic cell death, thus limiting yeast chronological lifespan; Checkpoint 7: Yeast chronological lifespan is shortened by “liponecrosis”, a mode of cell death that in chronologically “old” yeast cells is triggered due to (1) a reduced ability of mitochondria to generate ATP for the incorporation of non-esterified (“free”) fatty acids (FFA) into neutral lipids (NL); (2) a decline in the efficiency of an autophagic degradation of aged and dysfunctional mitochondria; and (3) a rise in the efficiencies with which mitochondria generate and release ROS. Activation arrows and inhibition bars denote pro-aging processes (displayed in blue color) or anti-aging processes (displayed in red color). See the text for additional details.

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References

    1. McBride H.M., Neuspiel M., Wasiak S. Mitochondria: More than just a powerhouse. Curr. Biol. 2006;16:R551–R560. doi: 10.1016/j.cub.2006.06.054. - DOI - PubMed
    1. Breitenbach M., Laun P., Dickinson J.R., Klocker A., Rinnerthaler M., Dawes I.W., Aung-Htut M.T., Breitenbach-Koller L., Caballero A., Nyström T., et al. The role of mitochondria in the aging processes of yeast. Subcell. Biochem. 2012;57:55–78. - PubMed
    1. Nunnari J., Suomalainen A. Mitochondria: In sickness and in health. Cell. 2012;148:1145–1159. doi: 10.1016/j.cell.2012.02.035. - DOI - PMC - PubMed
    1. Vafai S.B., Mootha V.K. Mitochondrial disorders as windows into an ancient organelle. Nature. 2012;491:374–383. doi: 10.1038/nature11707. - DOI - PubMed
    1. Pagliarini D.J., Rutter J. Hallmarks of a new era in mitochondrial biochemistry. Genes Dev. 2013;27:2615–2627. doi: 10.1101/gad.229724.113. - DOI - PMC - PubMed

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