Role of soluble adenylyl cyclase in mitochondria

Valsecchi, Federica; Konràd, Csaba; Manfredi, Giovanni

doi:10.1016/j.bbadis.2014.05.035

Cited by 54 publications

(64 citation statements)

References 81 publications

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“…Our results confirm previous studies [5,14,15,16] showing that PKA localized at an intermembrane space and matrix is the effector of cAMP, which modulates mitochondrial respiration via phosphorylation of electron transfer chain complexes (Figure 1A). cAMP is produced within mitochondria by a HCO 3 /CO 2 responsive soluble adenylyl cyclase, which couples CO 2 generation in the Krebs cycle with oxidative phosphorylation machinery activity [14,15]. In line, we first found that inhibition of sAC decreased ADP-coupled mitochondrial respiration, whereas the CO 2 -generating α-ketoglutarate dehydrogenase system stimulated CcOX-dependent respiration rates.…”

Section: Discussionsupporting

confidence: 92%

“…The direct role of cAMP-PKA signaling in regulation of mitochondrial oxidative phosphorylation has recently begun to emerge [5,14,15,16]. Central to this new paradigm is that cytosolic cAMP does not cross over the inner mitochondrial membrane.…”

Section: Introductionmentioning

confidence: 99%

“…Instead, elevation of mitochondrial cAMP is attributed to a unique form of mammalian soluble adenylyl cyclase (sAC) structurally, molecularly, and biochemically distinct from transmembrane adenylyl cyclase (tmAC). The sAC localized within the mitochondrial matrix is directly stimulated by CO 2 /HCO 3 − , but not by forskolin that only stimulates tmAC [14,16,17]. Numerous reports revealed that PKA localized at an intermembrane space and matrix was the effector of cAMP in mitochondria, which modulates respiration via phosphorylation of electron transfer chain complexes [18].…”

Section: Introductionmentioning

confidence: 99%

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Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction

Nevière

Delguste

Durand

et al. 2016

IJMS

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Adrenergic receptors couple to Gs-proteins leading to transmembrane adenylyl cyclase activation and cytosolic cyclic adenosine monophosphate (cAMP) production. Cyclic AMP is also produced in the mitochondrial matrix, where it regulates respiration through protein kinase A (PKA)-dependent phosphorylation of respiratory chain complexes. We hypothesized that a blunted mitochondrial cAMP-PKA pathway would participate in sepsis-induced heart dysfunction. Adult male mice were subjected to intra-abdominal sepsis. Mitochondrial respiration of cardiac fibers and myocardial contractile performance were evaluated in response to 8Br-cAMP, PKA inhibition (H89), soluble adenylyl cyclase inhibition (KH7), and phosphodiesterase inhibition (IBMX; BAY60-7550). Adenosine diphosphate (ADP)-stimulated respiratory rates of cardiac fibers were reduced in septic mice. Compared with controls, stimulatory effects of 8Br-cAMP on respiration rates were enhanced in septic fibers, whereas inhibitory effects of H89 were reduced. Ser-58 phosphorylation of cytochrome c oxidase subunit IV-1 was reduced in septic hearts. In vitro, incubation of septic cardiac fibers with BAY60-7550 increased respiratory control ratio and improved cardiac MVO2 efficiency in isolated septic heart. In vivo, BAY60-7550 pre-treatment of septic mice have limited impact on myocardial function. Mitochondrial cAMP-PKA signaling is impaired in the septic myocardium. PDE2 phosphodiesterase inhibition by BAY60-7550 improves mitochondrial respiration and cardiac MVO2 efficiency in septic mice.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction

Nevière

Delguste

Durand

et al. 2016

IJMS

View full text Add to dashboard Cite

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“…In multiple mammalian cell types, sAC activity reflects nutritional status linking metabolism with key biological processes including cellular motility [19], insulin secretion [14], and neuronal activity [20]. Furthermore, in a signaling cascade conserved from yeast to mammals, mitochondrial sAC senses metabolically produced CO 2 via HCO 3 − to regulate oxidative phosphorylation [21, 22]. These studies establish sAC as a pH/metabolic sensor in mammalian cells [14, 16, 17, 21–24].…”

Section: Introductionmentioning

confidence: 99%

The metabolic/pH sensor soluble adenylyl cyclase is a tumor suppressor protein

et al. 2016

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cAMP signaling pathways can both stimulate and inhibit the development of cancer; however, the sources of cAMP important for tumorigenesis remain poorly understood. Soluble adenylyl cyclase (sAC) is a non-canonical, evolutionarily conserved, nutrient- and pH-sensing source of cAMP. sAC has been implicated in the metastatic potential of certain cancers, and it is differentially localized in human cancers as compared to benign tissues. We now show that sAC expression is reduced in many human cancers. Loss of sAC increases cellular transformation in vitro and malignant progression in vivo. These data identify the metabolic/pH sensor soluble adenylyl cyclase as a previously unappreciated tumor suppressor protein.

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“…Phosphorylation of the mitochondrial OXPHOS complexes is mediated by protein kinases. At least some of the kinases are allosterically regulated by cyclic-AMP, which involves, among other ones, the action of a novel, mitochondrial-specific soluble adenylate cyclase (De Rasmo et al, 2015;Nowak & Bakajsova, 2015;Valsecchi, Konrad, & Manfredi, 2014;Valsecchi et al, 2013). As mentioned, the role of (reversible) phosphorylation of bacterial respiratory complexes is not understood, no more than possible signalling pathways either.…”

Section: Protein Phosphorylationmentioning

confidence: 99%

Bacterial Electron Transfer Chains Primed by Proteomics

Wessels¹,

Almeida²,

Kartal³

et al. 2016

Advances in Bacterial Electron Transport Systems and Their Regulation

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Electron transport phosphorylation is the central mechanism for most prokaryotic species to harvest energy released in the respiration of their substrates as ATP. Microorganisms have evolved incredible variations on this principle, most of these we perhaps do not know, considering that only a fraction of the microbial richness is known. Besides these variations, microbial species may show substantial versatility in using respiratory systems. In connection herewith, regulatory mechanisms control the expression of these respiratory enzyme systems and their assembly at the translational and posttranslational levels, to optimally accommodate changes in the supply of their energy substrates. Here, we present an overview of methods and techniques from the field of proteomics to explore bacterial electron transfer chains and their regulation at levels ranging from the whole organism down to the Ångstrom scales of protein structures. From the survey of the literature on this subject, it is concluded that proteomics, indeed, has substantially contributed to our comprehending of bacterial respiratory mechanisms, often in elegant combinations with genetic and biochemical approaches. However, we also note that advanced proteomics offers a wealth of opportunities, which have not been exploited at all, or at best underexploited in hypothesis-driving and hypothesis-driven research on bacterial bioenergetics. Examples obtained from the related area of mitochondrial oxidative phosphorylation research, where the application of advanced proteomics is more common, may illustrate these opportunities.

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Role of soluble adenylyl cyclase in mitochondria

Cited by 54 publications

References 81 publications

Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction

Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction

The metabolic/pH sensor soluble adenylyl cyclase is a tumor suppressor protein

Bacterial Electron Transfer Chains Primed by Proteomics

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