Cyclic AMP Produced inside Mitochondria Regulates Oxidative Phosphorylation

Acı́n-Pérez, Rebeca; Salazar, Eric; Kamenetsky, Margarita; Buck, Jochen; Levin, Lonny R.; Manfredi, Giovanni

doi:10.1016/j.cmet.2009.01.012

Cited by 416 publications

(560 citation statements)

References 54 publications

Supporting

Mentioning

519

Contrasting

Unclassified

Order By: Relevance

“…25 Recently, CA VB has been shown to convert the CO 2 produced by TCA cycle and b-oxidation to HCO 3 À which, in turn controls metabolic pathways increasing oxidative phosphorylation and reducing ROS generation. 31 Moreover, we speculate that the increased CA VB catalytic activity in SIRT3-overexpressing cells, by increasing HCO 3 À production, can buffer protons formed when ATP from cytosolic glycolysis is hydrolyzed by the F1F0 ATPase. 32 The net result of SIRT3 effects on HKII and CA VB is a tight control of pH i .…”

Section: Discussionmentioning

confidence: 99%

SIRT3 protects from hypoxia and staurosporine-mediated cell death by maintaining mitochondrial membrane potential and intracellular pH

et al. 2012

View full text Add to dashboard Cite

Mitochondrial sirtuin 3 (SIRT3) mediates cellular resistance toward various forms of stress. Here, we show that in mammalian cells subjected to hypoxia and staurosporine treatment SIRT3 prevents loss of mitochondrial membrane potential (DW mt ), intracellular acidification and reactive oxygen species accumulation. Our results indicate that: (i) SIRT3 inhibits mitochondrial permeability transition and loss of membrane potential by preventing HKII binding to the mitochondria, (ii) SIRT3 increases catalytic activity of the mitochondrial carbonic anhydrase VB, thereby preventing intracellular acidification, Bax activation and apoptotic cell death. In conclusion we propose that, in mammalian cells, SIRT3 has a central role in connecting changes in DW mt , intracellular pH and mitochondrial-regulated apoptotic pathways. Cell Death and Differentiation (2012) 19, 1815-1825 doi:10.1038/cdd.2012 published online 18 May 2012 Sirtuins are a family of protein highly conserved in both prokaryotes and eukaryotes. 1 The name derives from the Saccharomyces cerevisiae gene silent information regulator 2 (Sir2), the first known sirtuin, that, by silencing chromatin via deacetylation of histones, regulates both replicative and overall life span. 2 In mammals, seven Sir2 homologs, designated SIRT1 through SIRT7 have been identified, that regulate a wide range of intracellular processes including metabolism, longevity, aging, cancer and response to stress. 3-5 These proteins are characterized by an evolutionarily conserved sirtuin core domain 6 that contains the catalytic and nicotinamide adenine dinucleotide (NAD þ )-binding domain. Each sirtuin catalyzes protein deacetylation or adenosine diphosphate (ADP) ribosylation in vitro, requires NAD þ for enzymatic activity and generates nicotinamide, which then acts as a negative feedback inhibitor. 7 Because of the NAD þ requirement, sirtuins are categorized as class III histone deacetylases. 8 Mammalian sirtuins show distinct acetylated protein substrates and are localized in distinct subcellular compartments. Sirtuin 1 (SIRT1), SIRT6 and SIRT7 are in the nucleus, SIRT2 is primarily cytosolic and SIRT3, SIRT4 and SIRT5 are in the mitochondria. 9 Mitochondrial sirtuins participate in the regulation of ATP production, metabolism, apoptosis and cell signaling. 10 Among the three mitochondrial sirtuins, SIRT3 controls the global lysine acetylation of these organelles. 11 SIRT3 mediates cellular resistance toward various forms of stress by maintaining genomic stability and mitochondrial integrity. For example, SIRT3 influences cell survival by regulating the state of the mitochondrial permeability transition (MPT). However, the precise effects of SIRT3 on MPT are still not clear. In fact, some reports have shown that SIRT3 would deacetylate and inhibit the enzymatic activity of cyclophilin D 12 with the following dissociation from adenine nucleotide translocator, which, in turn, promotes detachment of hexokinase II (HKII) from voltage-dependent anion channel. Inhibition of cyclophilin D i...

show abstract

Section: Discussionmentioning

confidence: 99%

SIRT3 protects from hypoxia and staurosporine-mediated cell death by maintaining mitochondrial membrane potential and intracellular pH

et al. 2012

View full text Add to dashboard Cite

show abstract

“…In addition to these effector proteins, a complete cAMP signaling microdomain requires enzymes for synthesis and degradation of the second messenger. Although an intramitochondrial cAMP source has been identified recently (8), there is no known cAMP-degrading enzyme in this organelle. Cyclic AMP is formed inside mitochondria by soluble adenylyl cyclase (sAC) (8), a member of Class III of the nucleotidyl cyclase family, which also comprises the G-protein-regulated transmembrane adenylyl cyclases (13).…”

mentioning

confidence: 99%

“…Despite their importance, signaling into, from, and within mitochondria is still not well understood. Emerging signaling mechanisms in mitochondria and between the organelle and its environment include reversible protein deacetylation (3,4), redox regulation and reactive oxygen species formation (5-7), and cyclic adenosine monophosphate (cAMP) signaling (8,9). cAMP-dependent effects and proteins of cAMP signaling systems, such as cAMP-responsive element-binding protein (CREB), protein kinase A (PKA), and A-kinase anchoring proteins (AKAPs), 3 have been described in mitochondria (10 -12).…”

mentioning

confidence: 99%

A Phosphodiesterase 2A Isoform Localized to Mitochondria Regulates Respiration

Acı́n-Pérez

Russwurm

Günnewig

et al. 2011

Journal of Biological Chemistry

Self Cite

119

133

View full text Add to dashboard Cite

Mitochondria are central organelles in cellular energy metabolism, apoptosis, and aging processes. A signaling network regulating these functions was recently shown to include soluble adenylyl cyclase as a local source of the second messenger cAMP in the mitochondrial matrix. However, a mitochondrial cAMPdegrading phosphodiesterase (PDE) necessary for switching off this cAMP signal has not yet been identified. Here, we describe the identification and characterization of a PDE2A isoform in mitochondria from rodent liver and brain. We find that mitochondrial PDE2A is located in the matrix and that the unique N terminus of PDE2A isoform 2 specifically leads to mitochondrial localization of this isoform. Functional assays show that mitochondrial PDE2A forms a local signaling system with soluble adenylyl cyclase in the matrix, which regulates the activity of the respiratory chain. Our findings complete a cAMP signaling cascade in mitochondria and have implications for understanding the regulation of mitochondrial processes and for their pharmacological modulation.Mitochondria play central roles in cellular energy metabolism, as well as in the regulation of cell cycle progression, apoptosis, and aging processes (1, 2). Despite their importance, signaling into, from, and within mitochondria is still not well understood. Emerging signaling mechanisms in mitochondria and between the organelle and its environment include reversible protein deacetylation (3, 4), redox regulation and reactive oxygen species formation (5-7), and cyclic adenosine monophosphate (cAMP) signaling (8, 9).cAMP-dependent effects and proteins of cAMP signaling systems, such as cAMP-responsive element-binding protein (CREB), protein kinase A (PKA), and A-kinase anchoring proteins (AKAPs), 3 have been described in mitochondria (10 -12). In addition to these effector proteins, a complete cAMP signaling microdomain requires enzymes for synthesis and degradation of the second messenger. Although an intramitochondrial cAMP source has been identified recently (8), there is no known cAMP-degrading enzyme in this organelle. Cyclic AMP is formed inside mitochondria by soluble adenylyl cyclase (sAC) (8), a member of Class III of the nucleotidyl cyclase family, which also comprises the G-protein-regulated transmembrane adenylyl cyclases (13). Unique from transmembrane adenylyl cyclases, sAC is activated by bicarbonate (14), and it appears to act as a metabolic sensor (15), whose mitochondrial form(s) seems to modulate PKA-mediated regulation of respiration (8) and apoptosis (16).The opponents of the cyclic nucleotide-forming cyclases are cyclic nucleotide monophosphate (cNMP)-degrading phosphodiesterases (PDEs). Mammalian cells contain a varying subset of members of the classical PDE family, which comprises 11 PDE gene families (PDE1-11) (17, 18) and non-generic PDEs such as the protein human Prune (19,20). The isoforms of the generic PDEs comprise homologous catalytic domains, fused to varying regulatory domains, making them sensitive to a variety of signals s...

show abstract

“…Moreover, it was recently shown that cyclic AMP, which activates mitochondrial protein kinase A, does not originate from cytoplasmic sources but is generated within the mitochondrion by the carbon dioxide/ bicarbonate-regulated soluble mitochondrial adenylyl cyclase in response to metabolically generated carbon dioxide. 23 In the latter report, it was demonstrated for the first time that a complete protein kinase A signaling pathway resides within this organelle. This pathway is believed to function as a metabolic sensor, modulating adenosine triphosphate production in response to metabolic needs by mitochondrial protein kinase A-mediated regulation of respiratory chain activity.…”

Section: Genes and Signaling Pathways In Batmentioning

confidence: 99%

Brown adipose tissue in humans

Enerbäck

2010

Int J Obes

View full text Add to dashboard Cite

Obesity is endemic in many regions of the world and a forerunner of several serious and sometimes fatal diseases such as ischemic heart disease, stroke, kidney failure and neoplasia. Although we know its originFit results when energy intake exceeds energy expenditureFat present, the only proven therapy is bariatric surgery. This is a major abdominal procedure that, for reasons that are largely unknown (it cannot be explained solely by a reduction in ventricular volume), significantly reduces energy intake, but because of cost and limited availability, it will most likely be reserved for only a small fraction of those who stand to gain from effective antiobesity treatment. Clearly, alternative ways to treat obesity are needed. Another way to combat excessive accumulation of white adipose tissue would be to increase energy expenditure. Rodents, hibernators and human infants all have a specialized tissueFbrown adipose tissue (BAT)Fwith the unique capacity to regulate energy expenditure by a process called adaptive thermogenesis. This process depends on the expression of uncoupling protein-1 (UCP1), which is a unique marker for BAT. UCP1 is an inner mitochondrial membrane protein that short circuits the mitochondrial proton gradient, so that oxygen consumption is no longer coupled to adenosine triphosphate synthesis. As a consequence, heat is generated. Mice lacking ucp-1 are severely compromised in their ability to maintain normal body temperature when acutely exposed to cold and they are also prone to become obese. We have shown that, in mice, BAT protects against diet-induced obesity, insulin resistance and type 2 diabetes. This is based on prevention of excessive accumulation of triglyceride in non-adipose tissues such as muscle and liver. Ectopic triglyceride storage at these locations is associated with initiation of insulin resistance and, ultimately, development of type 2 diabetes.

show abstract

Cyclic AMP Produced inside Mitochondria Regulates Oxidative Phosphorylation

Cited by 416 publications

References 54 publications

SIRT3 protects from hypoxia and staurosporine-mediated cell death by maintaining mitochondrial membrane potential and intracellular pH

SIRT3 protects from hypoxia and staurosporine-mediated cell death by maintaining mitochondrial membrane potential and intracellular pH

A Phosphodiesterase 2A Isoform Localized to Mitochondria Regulates Respiration

Brown adipose tissue in humans

Contact Info

Product

Resources

About