Mitochondrial Respiratory Thresholds Regulate Yeast Chronological Life Span and its Extension by Caloric Restriction

Ocampo, Alejandro; Liu, Jingjing; Schroeder, Elizabeth A.; Shadel, Gerald S.; Barrientos, Antoni

doi:10.1016/j.cmet.2012.05.013

Cited by 166 publications

(251 citation statements)

References 40 publications

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“…These data support a recent model (11,38,39) postulating the existence of a transient, adaptive ROS signal necessary for survival in stationary phase in TOR signaling mutants. Our novel finding is the identification of an upstream, mitochondrion-localized, modulator of TOR signaling.…”

Section: Discussionsupporting

confidence: 78%

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Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses

Bohovych

Kastora

Christianson

et al. 2016

Molecular and Cellular Biology

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A network of conserved proteases known as the intramitochondrial quality control (IMQC) system is central to mitochondrial protein homeostasis and cellular health. IMQC proteases also appear to participate in establishment of signaling cues for mitochondrion-to-nucleus communication. However, little is known about this process. Here, we show that in Saccharomyces cerevisiae, inactivation of the membrane-bound IMQC protease Oma1 interferes with oxidative-stress responses through enhanced production of reactive oxygen species (ROS) during logarithmic growth and reduced stress signaling via the TORC1-Rim15-Msn2/Msn4 axis. Pharmacological or genetic prevention of ROS accumulation in Oma1-deficient cells restores this defective TOR signaling. Additionally, inactivation of the Oma1 ortholog in the human fungal pathogen Candida albicans also alters TOR signaling and, unexpectedly, leads to increased resistance to neutrophil killing and virulence in the invertebrate animal model Galleria mellonella. Our findings reveal a novel and evolutionarily conserved link between IMQC and TOR-mediated signaling that regulates physiological plasticity and pancellular oxidative-stress responses. Mounting evidence indicates that mitochondrial processes are tightly integrated with cellular signaling pathways (1-3). Such integration enables rapid modulation of mitochondrial functions upon homeostatic fluctuations in the intra-and extracellular environment and adaptation of cellular metabolism in response to changes within the mitochondrion. Studies in Saccharomyces cerevisiae have been instrumental for the elucidation of evolutionarily conserved aspects of mitochondrion-linked signaling. These analyses also provided insights into the mechanisms by which cells in general and mitochondria in particular are protected from oxidative insults (4).Reactive oxygen species (ROS), a by-product of mitochondrial respiration, can damage a number of biological molecules, thereby affecting mitochondrial and cellular well-being (5, 6). Accumulating ROS-elicited oxidative stress and damage have long been known to be detrimental factors in many pathologies and aging (5,7,8). On the other hand, many ROS are now recognized as signaling molecules essential in multiple pathways, including mitochondrion-nucleus communication and longevity regulation (2, 6). The phenomenon, known as ROS adaptation, preconditioning, or hormesis, is believed to be one of the ways by which reduced signaling via the TOR pathway leads to stress-protective effects (2, 9). This effect partly stems from the derepression, through TOR inhibition, of the downstream signaling branch of the TOR pathway that includes the kinase Rim15 and a stress/ nutrient signaling node containing the transcription factors Gis1 and the functionally redundant Msn2/Msn4 pair (4, 10). ROS adaptation requires respiration and is temporally restricted to logarithmic and diauxic growth phases (11).A network of conserved proteases known as intramitochondrial quality control (IMQC) is central to normal mitochondria...

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Section: Discussionsupporting

confidence: 78%

“…Mitochondria generate cues that regulate a number of cellular processes, including oxidative-stress tolerance (11,(37)(38)(39)(40). Mitochondrion-emitted ROS appear to be central to many of these events (6).…”

Section: Resultsmentioning

confidence: 99%

Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses

Bohovych

Kastora

Christianson

et al. 2016

Molecular and Cellular Biology

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“…Caloric restriction (CR) is a classical example of energy scarcity. CR up to 40% of nutritious diet intake extends healthy lifespan from yeast to mammals (Colman et al, 2014;Wei et al, 2008), delays the onset of multiple age-associated diseases, and improves metabolic health (De Guzman et al, 2013;Ocampo et al, 2012). The beneficial effects of CR are chiefly mediated by the reduced energy intake, which affects the ration of cellular substrates, such as NAD + /NAD and AMP/ATP, and triggers downstream changes in several energy-sensing pathways (Cantó and Auwerx, 2011).…”

Section: Introductionmentioning

confidence: 99%

Caloric Restriction Leads to Browning of White Adipose Tissue through Type 2 Immune Signaling

et al. 2016

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SUMMARYCaloric restriction (CR) extends lifespan from yeast to mammals, delays onset of age-associated diseases, and improves metabolic health. We show that CR stimulates development of functional beige fat within the subcutaneous and visceral adipose tissue, contributing to decreased white fat and adipocyte size in lean C57BL/6 and BALB/c mice kept at room temperature or at thermoneutrality and in obese leptin-deficient mice. These metabolic changes are mediated by increased eosinophil infiltration, type 2 cytokine signaling, and M2 macrophage polarization in fat of CR animals. Suppression of the type 2 signaling, using Il4ra À/À , Stat6 À/À , or mice transplanted with Stat6 À/À bone marrow-derived hematopoietic cells, prevents the CR-induced browning and abrogates the subcutaneous fat loss and the metabolic improvements induced by CR. These results provide insights into the overall energy homeostasis during CR, and they suggest beige fat development as a common feature in conditions of negative energy balance.

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“…The efficient utilization of resources is ensured by the activation of mitochondrial respiration. It has been proved that the utilization of carbohydrate stores by respiration instead of glycolysis extends the life span (10,11), and mitochondrial dysfunctions cause its shortening (12). Endosome movement, selective types of autophagy, and the quality control of mitochondria are engaged in by the actin cytoskeleton (13)(14)(15).…”

mentioning

confidence: 99%

The Stationary-Phase Cells of Saccharomyces cerevisiae Display Dynamic Actin Filaments Required for Processes Extending Chronological Life Span

Vašicová

Lejskova

Malcová

et al. 2015

Molecular and Cellular Biology

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Stationary-growth-phase Saccharomyces cerevisiae yeast cultures consist of nondividing cells that undergo chronological aging. For their successful survival, the turnover of proteins and organelles, ensured by autophagy and the activation of mitochondria, is performed. Some of these processes are engaged in by the actin cytoskeleton. In S. cerevisiae stationary-phase cells, F actin has been shown to form static aggregates named actin bodies, subsequently cited to be markers of quiescence. Our in vivo analyses revealed that stationary-phase cultures contain cells with dynamic actin filaments, besides the cells with static actin bodies. The cells with dynamic actin displayed active endocytosis and autophagy and well-developed mitochondrial networks. Even more, stationary-phase cell cultures grown under calorie restriction predominantly contained cells with actin cables, confirming that the presence of actin cables is linked to successful adaptation to stationary phase. Cells with actin bodies were inactive in endocytosis and autophagy and displayed aberrations in mitochondrial networks. Notably, cells of the respiratory activity-deficient cox4⌬ strain displayed the same mitochondrial aberrations and actin bodies only. Additionally, our results indicate that mitochondrial dysfunction precedes the formation of actin bodies and the appearance of actin bodies corresponds to decreased cell fitness. We conclude that the F-actin status reflects the extent of damage that arises from exponential growth.O nce glucose and other external nutrients are exhausted, cell division stops and Saccharomyces cerevisiae cells are able to survive for extended periods of time. This period of survival has been termed chronological aging and has become a model for aging of postmitotic tissues (1, 2). The cells in these nondividing stationary-phase cell cultures are often termed quiescent (Q) cells (3, 4). Some authors claim that stationary-phase yeast cell populations are heterogeneous and only a portion of them have characteristics of quiescence (5, 6). The ability to survive the period of scarcity of external nutrition and reproduce again upon refeeding is influenced by several life span-extending genetic and environmental interventions. One of the most cited is calorie restriction (CR) (7).In general, cells that are in a nutrient-poor environment activate processes that help them to efficiently utilize inner resources and thus prolong the life span. A catabolic process that has a positive impact on chronological aging is autophagy, which provides nutrients by the vacuolar degradation of damaged or superfluous macromolecules and organelles (8, 9). In addition, Fabrizio et al. demonstrated that the deletion of several genes encoding endosomal functions also shortens the life span (8). Note that some of them have not been directly implicated in autophagy (8). The efficient utilization of resources is ensured by the activation of mitochondrial respiration. It has been proved that the utilization of carbohydrate stores by respiration instead...

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Mitochondrial Respiratory Thresholds Regulate Yeast Chronological Life Span and its Extension by Caloric Restriction

Cited by 166 publications

References 40 publications

Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses

Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses

Caloric Restriction Leads to Browning of White Adipose Tissue through Type 2 Immune Signaling

The Stationary-Phase Cells of Saccharomyces cerevisiae Display Dynamic Actin Filaments Required for Processes Extending Chronological Life Span

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