Mitochondrial cAMP exerts positive feedback on mitochondrial Ca2+ uptake via the recruitment of Epac1

Szanda, Gergö; Wisniewski, Éva; Rajki, Anikó; Spät, András

doi:10.1242/jcs.215178

Cited by 16 publications

(18 citation statements)

References 62 publications

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“…This may suggest that our FRET system does not have sufficient spatial resolution to detect discrete microdomains of cAMP (44), that the size of the cAMP increase is below the limit of detection, or that cAMP increases in mitochondria and not in the cytosol. This last hypothesis would be supported by a recent paper that showed that aldosterone increases selectively the activity of the soluble adenylyl cyclase in the mitochondria and that the inhibition of EPAC reduced mitochondrial Ca 2ϩ uptake, in a similar fashion to what was observed in the present contribution (45). It would be unlikely that EPAC, instead, is activated in a cAMP-independent fashion as this has never been reported previously.…”

Section: Htas2r46 Regulates Mitochondrial Calcium Bufferingsupporting

confidence: 88%

Absinthin, an agonist of the bitter taste receptor hTAS2R46, uncovers an ER-to-mitochondria Ca2+–shuttling event

Talmon

Rossi

Lim

et al. 2019

Journal of Biological Chemistry

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Type 2 taste receptors (TAS2R) are G protein-coupled receptors first described in the gustatory system, but have also been shown to have extraoral localizations, including airway smooth muscle (ASM) cells, in which TAS2R have been reported to induce relaxation. TAS2R46 is an unexplored subtype that responds to its highly specific agonist absinthin. Here, we first demonstrate that, unlike other bitter-taste receptor agonists, absinthin alone (1 M) in ASM cells does not induce Ca 2؉ signals but reduces histamine-induced cytosolic Ca 2؉ increases. To investigate this mechanism, we introduced into ASM cells aequorin-based Ca 2؉ probes targeted to the cytosol, subplasma membrane domain, or the mitochondrial matrix. We show that absinthin reduces cytosolic histamine-induced Ca 2؉ rises and simultaneously increases Ca 2؉ influx into mitochondria. We found that this effect is inhibited by the potent human TAS2R46 (hTAS2R46) antagonist 3␤-hydroxydihydrocostunolide and is no longer evident in hTAS2R46-silenced ASM cells, indicating that it is hTAS2R46-dependent. Furthermore, these changes were sensitive to the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenyl-hydrazone (FCCP); the mitochondrial calcium uniporter inhibitor KB-R7943 (carbamimidothioic acid); the cytoskeletal disrupter latrunculin; and an inhibitor of the exchange protein directly activated by cAMP (EPAC), ESI-09. Similarly, the ␤2 agonist salbutamol also could induce Ca 2؉ shuttling from cytoplasm to mitochondria, suggesting that this new mechanism might be generalizable. Moreover, forskolin and an EPAC activator mimicked this effect in HeLa cells. Our findings support the hypothesis that plasma membrane receptors can positively regulate mitochondrial Ca 2؉ uptake, adding a further facet to the ability of cells to encode complex Ca 2؉ signals. This work was supported by Regione Piemonte Grant on Autoimmunity and Allergic Diseases D.D. n.195 18/07/2014 (to L. G. F.). The authors declare that they have no conflicts of interest with the contents of this article. This article contains supporting Experimental procedures and Figs. S1-S6.

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Section: Htas2r46 Regulates Mitochondrial Calcium Bufferingsupporting

confidence: 88%

Absinthin, an agonist of the bitter taste receptor hTAS2R46, uncovers an ER-to-mitochondria Ca2+–shuttling event

Talmon

Rossi

Lim

et al. 2019

Journal of Biological Chemistry

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“…EPAC1 in mitochondria has gained increased attention recently and has been suggested to play a role in regulating MCU activity in H295R adrenocortical cells and HeLa cells as well as MCU activity and OXPHOS activity in isolated cardiac mitochondria from mouse (Szanda, Wisniewski, Rajki, & Spät, ; Wang et al, ). EPAC1 has not yet been demonstrated in brain mitochondria (to our knowledge), but here we provide pharmacological evidence for its functional presence.…”

Section: Discussionmentioning

confidence: 99%

“…and OXPHOS activity in isolated cardiac mitochondria from mouse (Szanda, Wisniewski, Rajki, & Spät, 2018;Wang et al, 2016). EPAC1…”

Section: H295r Adrenocortical Cells and Hela Cells As Well As Mcu Actmentioning

confidence: 99%

Soluble adenylyl cyclase‐mediated cAMP signaling and the putative role of PKA and EPAC in cerebral mitochondrial function

Jakobsen

Lange

Bak

2019

J of Neuroscience Research

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Mitochondria produce the bulk of the ATP in most cells, including brain cells. Regulating this complex machinery to match the energetic needs of the cell is a complicated process that we have yet to understand in its entirety. In this context, 3′,5′‐cyclic AMP (cAMP) has been suggested to play a seminal role in signaling‐metabolism coupling and regulation of mitochondrial ATP production. In cells, cAMP signals may affect mitochondria from the cytosolic side but more recently, a cAMP signal produced within the matrix of mitochondria by soluble adenylyl cyclase (sAC) has been suggested to regulate respiration and thus ATP production. However, little is known about these processes in brain mitochondria, and the effectors of the cAMP signal generated within the matrix are not completely clear since both protein kinase A (PKA) and exchange protein activated by cAMP 1 (EPAC1) have been suggested to be involved. Here, we review the current knowledge and relate it to brain mitochondria. Further, based on measurements of respiration, membrane potential, and ATP production in isolated mouse brain cortical mitochondria we show that inhibitors of sAC, PKA, or EPAC affect mitochondrial function in distinct ways. In conclusion, we suggest that brain mitochondria do regulate their function via sAC‐mediated cAMP signals and that both PKA and EPAC could be involved downstream of sAC. Finally, due to the role of faulty mitochondrial function in a range of neurological diseases, we expect that the function of sAC‐cAMP‐PKA/EPAC signaling in brain mitochondria will likely attract further attention.

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“…Importantly, cAMP has recently emerged as a potent regulator of mitochondrial metabolism. The mitochondrial matrix holds a unique cellular cAMP nanodomain independent of the cytosol [ 16 , 17 ], and its targeting has been even implicated in the preservation of cardiomyocyte function [ 18 ]. Mitochondrial cAMP nanodomains seem to embrace a unique subset of members of the adenylyl cyclase (AC) family — the soluble AC (sAC) [ 16 , 19 ] — and the phosphodiesterase (PDE) family — the dual-specific PDE2, the latter has been linked to both cardiac and lung injury models [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…The mitochondrial matrix holds a unique cellular cAMP nanodomain independent of the cytosol [ 16 , 17 ], and its targeting has been even implicated in the preservation of cardiomyocyte function [ 18 ]. Mitochondrial cAMP nanodomains seem to embrace a unique subset of members of the adenylyl cyclase (AC) family — the soluble AC (sAC) [ 16 , 19 ] — and the phosphodiesterase (PDE) family — the dual-specific PDE2, the latter has been linked to both cardiac and lung injury models [ 20 , 21 ]. Next to sAC and PDE2, the exchange protein directly activated by cAMP (Epac)1 [ 19 , 22 ], and the A-kinase anchoring family member AKAP1 also maintain mitochondrial function [ 23 ] ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

Nanodomains in cardiopulmonary disorders and the impact of air pollution

Cattani‐Cavalieri

Valença

Schmidt

2020

Biochemical Society Transactions

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Air pollution is a major environmental threat and each year about 7 million people reported to die as a result of air pollution. Consequently, exposure to air pollution is linked to increased morbidity and mortality world-wide. Diesel automotive engines are a major source of urban air pollution in the western societies encompassing particulate matter and diesel exhaust particles (DEP). Air pollution is envisioned as primary cause for cardiovascular dysfunction, such as ischemic heart disease, cardiac dysrhythmias, heart failure, cerebrovascular disease and stroke. Air pollution also causes lung dysfunction, such as chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and specifically exacerbations of these diseases. DEP induces inflammation and reactive oxygen species production ultimately leading to mitochondrial dysfunction. DEP impair structural cell function and initiate the epithelial-to-mesenchymal transition, a process leading to dysfunction in endothelial as well as epithelial barrier, hamper tissue repair and eventually leading to fibrosis. Targeting cyclic adenosine monophosphate (cAMP) has been implicated to alleviate cardiopulmonary dysfunction, even more intriguingly cAMP seems to emerge as a potent regulator of mitochondrial metabolism. We propose that targeting of the mitochondrial cAMP nanodomain bear the therapeutic potential to diminish air pollutant — particularly DEP — induced decline in cardiopulmonary function.

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Mitochondrial cAMP exerts positive feedback on mitochondrial Ca2+ uptake via the recruitment of Epac1

Cited by 16 publications

References 62 publications

Absinthin, an agonist of the bitter taste receptor hTAS2R46, uncovers an ER-to-mitochondria Ca2+–shuttling event

Absinthin, an agonist of the bitter taste receptor hTAS2R46, uncovers an ER-to-mitochondria Ca2+–shuttling event

Soluble adenylyl cyclase‐mediated cAMP signaling and the putative role of PKA and EPAC in cerebral mitochondrial function

Nanodomains in cardiopulmonary disorders and the impact of air pollution

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