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Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling.

ABSTRACT: Sirtuins are a highly conserved family of proteins whose activity can prolong the lifespan of model organisms such as yeast, worms and flies. Mammals contain seven sirtuins (SIRT1-7) that modulate distinct metabolic and stress response pathways. Three sirtuins, SIRT3, SIRT4 and SIRT5, are located in the mitochondria, dynamic organelles that function as the primary site of oxidative metabolism and play crucial roles in apoptosis and intracellular signaling. Recent findings have shed light on how the mitochondrial sirtuins function in the control of basic mitochondrial biology, including energy production, metabolism, apoptosis and intracellular signaling.

SUBMITTER: Verdin E

PROVIDER: S-EPMC2992946 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling.

Verdin Eric E Hirschey Matthew D MD Finley Lydia W S LW Haigis Marcia C MC

Trends in biochemical sciences 20100920 12

Sirtuins are a highly conserved family of proteins whose activity can prolong the lifespan of model organisms such as yeast, worms and flies. Mammals contain seven sirtuins (SIRT1-7) that modulate distinct metabolic and stress response pathways. Three sirtuins, SIRT3, SIRT4 and SIRT5, are located in the mitochondria, dynamic organelles that function as the primary site of oxidative metabolism and play crucial roles in apoptosis and intracellular signaling. Recent findings have shed light on how ...[more]

PMID: 20863707

Similar Datasets

cAMP/PKA signaling balances respiratory activity with mitochondria dependent apoptosis via transcriptional regulation

Project description:This data provides evidence that elevation of cAMP levels has a dramatic effect on the transcriptome of yeast cells, with particular emphasis on mitochondrial function and the promotion of ROS production S. cerevisiae cells lacking the high affinity phosphodiesterase PDE2or both PDE2 and the PKA subunit TPK3 were grown for 24h in rich media in the presence of 4mM exogensously added cAMP. 8 samples.

2010-11-24 | E-GEOD-25541 | biostudies-arrayexpress

cAMP/PKA signaling balances respiratory activity with mitochondria dependent apoptosis via transcriptional regulation.

Project description:BACKGROUND:Appropriate control of mitochondrial function, morphology and biogenesis are crucial determinants of the general health of eukaryotic cells. It is therefore imperative that we understand the mechanisms that co-ordinate mitochondrial function with environmental signaling systems. The regulation of yeast mitochondrial function in response to nutritional change can be modulated by PKA activity. Unregulated PKA activity can lead to the production of mitochondria that are prone to the production of ROS, and an apoptotic form of cell death. RESULTS:We present evidence that mitochondria are sensitive to the level of cAMP/PKA signaling and can respond by modulating levels of respiratory activity or committing to self execution. The inappropriate activation of one of the yeast PKA catalytic subunits, Tpk3p, is sufficient to commit cells to an apoptotic death through transcriptional changes that promote the production of dysfunctional, ROS producing mitochondria. Our data implies that cAMP/PKA regulation of mitochondrial function that promotes apoptosis engages the function of multiple transcription factors, including HAP4, SOK2 and SCO1. CONCLUSIONS:We propose that in yeast, as is the case in mammalian cells, mitochondrial function and biogenesis are controlled in response to environmental change by the concerted regulation of multiple transcription factors. The visualization of cAMP/TPK3 induced cell death within yeast colonies supports a model that PKA regulation plays a physiological role in coordinating respiratory function and cell death with nutritional status in budding yeast.

| S-EPMC3001716 | biostudies-literature

cAMP/PKA signaling balances respiratory activity with mitochondria dependent apoptosis via transcriptional regulation

2010-11-24 | GSE25541 | GEO

Sirtuin 7 Regulates Nitric Oxide Production and Apoptosis to Promote Mycobacterial Clearance in Macrophages.

Project description:The host immune system plays a pivotal role in the containment of Mycobacterium tuberculosis (Mtb) infection, and host-directed therapy (HDT) is emerging as an effective strategy to treat tuberculosis (TB), especially drug-resistant TB. Previous studies revealed that expression of sirtuin 7 (SIRT7), a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, was downregulated in macrophages after Mycobacterial infection. Inhibition of SIRT7 with the pan-sirtuin family inhibitor nicotinamide (NAM), or by silencing SIRT7 expression, promoted intracellular growth of Mtb and restricted the generation of nitric oxide (NO). Addition of the exogenous NO donor SNAP abrogated the increased bacterial burden in NAM-treated or SIRT7-silenced macrophages. Furthermore, SIRT7-silenced macrophages displayed a lower frequency of early apoptotic cells after Mycobacterial infection, and this could be reversed by providing exogenous NO. Overall, this study clarified a SIRT7-mediated protective mechanism against Mycobacterial infection through regulation of NO production and apoptosis. SIRT7 therefore has potential to be exploited as a novel effective target for HDT of TB.

| S-EPMC8678072 | biostudies-literature

Sirtuin catalysis and regulation.

Project description:Sirtuins are a family of NAD(+)-dependent protein deacetylases/deacylases that dynamically regulate transcription, metabolism, and cellular stress response. Their general positive link with improved health span in mammals, potential regulation of pathways mediated by caloric restriction, and growing links to human disease have spurred interest in therapeutics that target their functions. Here, we review the current understanding of the chemistry of catalysis, biological targets, and endogenous regulation of sirtuin activity. We discuss recent efforts to generate small-molecule regulators of sirtuin activity.

| S-EPMC3522242 | biostudies-literature

Aurora kinase A localises to mitochondria to control organelle dynamics and energy production.

Project description:Many epithelial cancers show cell cycle dysfunction tightly correlated with the overexpression of the serine/threonine kinase Aurora A (AURKA). Its role in mitotic progression has been extensively characterised, and evidence for new AURKA functions emerges. Here, we reveal that AURKA is located and imported in mitochondria in several human cancer cell lines. Mitochondrial AURKA impacts on two organelle functions: mitochondrial dynamics and energy production. When AURKA is expressed at endogenous levels during interphase, it induces mitochondrial fragmentation independently from RALA. Conversely, AURKA enhances mitochondrial fusion and ATP production when it is over-expressed. We demonstrate that AURKA directly regulates mitochondrial functions and that AURKA over-expression promotes metabolic reprogramming by increasing mitochondrial interconnectivity. Our work paves the way to anti-cancer therapeutics based on the simultaneous targeting of mitochondrial functions and AURKA inhibition.

| S-EPMC6140714 | biostudies-literature

Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production.

Project description:Although many types of ancient bacteria and archea rely on hydrogen sulfide (H(2)S) for their energy production, eukaryotes generate ATP in an oxygen-dependent fashion. We hypothesize that endogenous H(2)S remains a regulator of energy production in mammalian cells under stress conditions, which enables the body to cope with energy demand when oxygen supply is insufficient. Cystathionine ?-lyase (CSE) is a major H(2)S-producing enzyme in the cardiovascular system that uses cysteine as the main substrate. Here we show that CSE is localized only in the cytosol, not in mitochondria, of vascular smooth-muscle cells (SMCs) under resting conditions, revealed by Western blot analysis and confocal microscopy of SMCs transfected with GFP-tagged CSE plasmid. After SMCs were exposed to A23187, thapsigargin, or tunicamycin, intracellular calcium level was increased, and CSE translocated from the cytosol to mitochondria. CSE was coimmunoprecipitated with translocase of the outer membrane 20 (Tom20) in mitochondrial membrane. Tom20 siRNA significantly inhibited mitochondrial translocation of CSE and mitochondrial H(2)S production. The cysteine level inside mitochondria is approximately three times that in the cytosol. Translocation of CSE to mitochondria metabolized cysteine, produced H(2)S inside mitochondria, and increased ATP production. Inhibition of CSE activity reversed A23187-stimulated mitochondrial ATP production. H(2)S improved mitochondrial ATP production in SMCs with hypoxia, which alone decreased ATP production. These results suggest that translocation of CSE to mitochondria on specific stress stimulations is a unique mechanism to promote H(2)S production inside mitochondria, which subsequently sustains mitochondrial ATP production under hypoxic conditions.

| S-EPMC3287003 | biostudies-literature

TAp63alpha induces apoptosis by activating signaling via death receptors and mitochondria.

Project description:TP63, an important epithelial developmental gene, has significant homology to p53. Unlike p53, the expression of p63 is regulated by two different promoters resulting in proteins with opposite functions: the full-length transcriptionally active TAp63 and the dominant-negative DeltaNp63. We investigated the downstream mechanisms by which TAp63alpha elicits apoptosis. TAp63alpha directly transactivates the CD95 gene via the p53 binding site in the first intron resulting in upregulation of a functional CD95 death receptor. Stimulation and blocking experiments of the CD95, TNF-R and TRAIL-R death receptor systems revealed that TAp63alpha can trigger expression of each of these death receptors. Furthermore, our findings demonstrate a link between TAp63alpha and the mitochondrial apoptosis pathway. TAp63alpha upregulates expression of proapoptotic Bcl-2 family members like Bax and BCL2L11 and the expression of RAD9, DAP3 and APAF1. Of clinical relevance is the fact that TAp63alpha is induced by many chemotherapeutic drugs and that inhibiting TAp63 function leads to chemoresistance. Thus, beyond its importance in development and differentiation, we describe an important role for TAp63alpha in the induction of apoptosis and chemosensitivity.

| S-EPMC1173149 | biostudies-literature

Neuronal ROS signaling rather than AMPK/sirtuin-mediated energy sensing links dietary restriction to lifespan extension.

Project description:Dietary restriction (DR) extends lifespan and promotes metabolic health in evolutionary distinct species. DR is widely believed to promote longevity by causing an energy deficit leading to increased mitochondrial respiration. We here show that inhibitors of mitochondrial complex I promote physical activity, stress resistance as well as lifespan of Caenorhabditis elegans despite normal food uptake, i.e. in the absence of DR. However, complex I inhibition does not further extend lifespan in dietarily restricted nematodes, indicating that impaired complex I activity mimics DR. Promotion of longevity due to complex I inhibition occurs independently of known energy sensors, including DAF-16/FoxO, as well as AAK-2/AMPK and SIR-2.1/sirtuins, or both. Consistent with the concept of mitohormesis, complex I inhibition transiently increases mitochondrial formation of reactive oxygen species (ROS) that activate PMK-1/p38 MAP kinase and SKN-1/NRF-2. Interference with this retrograde redox signal as well as ablation of two redox-sensitive neurons in the head of the worm similarly prevents extension of lifespan. These findings unexpectedly indicate that DR extends organismal lifespan through transient neuronal ROS signaling rather than sensing of energy depletion, providing unexpected pharmacological options to promote exercise capacity and healthspan despite unaltered eating habits.

| S-EPMC3817383 | biostudies-literature

Endoplasmic Reticulum Interaction Supports Energy Production and Redox Homeostasis in Mitochondria Released from Astrocytes.

Project description:Mitochondria can be released by astrocytes as part of a help-me signaling process in stroke. In this study, we investigated the molecular mechanisms that underlie mitochondria secretion, redox status, and functional regulation in the extracellular environment. Exposure of rat primary astrocytes to NAD or cADPR elicited an increase in mitochondrial calcium through ryanodine receptor (RyR) in the endoplasmic reticulum (ER). Importantly, CD38 stimulation with NAD accelerated ATP production along with increasing glutathione reductase (GR) and dipicolinic acid (DPA) in intracellular mitochondria. When RyR was blocked by Dantrolene, all effects were clearly diminished. Mitochondrial functional assay showed that these activated mitochondria appeared to be resistant to H2O2 exposure and sustained mitochondrial membrane potential, while inhibition of RyR resulted in disrupted membrane potential under oxidative stress. Finally, a gain- or loss-of-function assay demonstrated that treatment with DPA in control mitochondria preserved GR contents and increased mitochondrial membrane potential, whereas inhibiting GR with carmustine decreased membrane potentials in extracellular mitochondria released from astrocytes. Collectively, these data suggest that ER-mitochondrial interaction mediated by CD38 stimulation may support mitochondrial energy production and redox homeostasis during the mode of mitochondrial transfer from astrocytes.

| S-EPMC8324082 | biostudies-literature

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