Phosphatases control PKA-dependent functional microdomains at the outer mitochondrial membrane

Burdyga, Alex; Surdo, Nicoletta C.; Monterisi, Stefania; Benedetto, Giulietta Di; Grisan, Francesca; Penna, Elisa; Pellegrini, Luca; Zaccolo, Manuela; Bortolozzi, Mario; Swietach, Pawel; Pozzan, Tullio; Lefkimmiatis, Konstantinos

doi:10.1073/pnas.1806318115

Cited by 43 publications

(49 citation statements)

References 54 publications

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“…However, no PKA activity was observed in HeLa or HEK cells, when treated with bicarbonate or a PKA agonist (Lefkimmiatis et al, ). Similar results were obtained by Burdyga and colleagues who observed no cAMP/PKA‐mediated phosphorylation in the matrix or IMS but only at the OMM in neonatal rat ventricular myocytes (NRVM) and HeLa cells (Burdyga et al, ). Furthermore, Monterisi and colleagues found no presence of PDE2A in the mitochondrial matrix, but only at the IMM and OMM in NRVM and HeLa cells (Monterisi et al, ).…”

Section: Introductionsupporting

confidence: 86%

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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Section: Introductionsupporting

confidence: 86%

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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“…Finally, in cardiomyocytes, cyclic AMP (cAMP) and Ca 2+ signaling are well known to intersect and modulate with each other (reviewed in Filadi et al, 2017a). Interestingly, recently, in neonatal rat ventricular cardiomyocytes, the presence of a compartmentalized cAMP-PKA signal at the OMM has been demonstrated (Burdyga et al, 2018). Whether the narrow gap between SR and OMM might further shape this localized pathway will require further investigations.…”

Section: Physiological Significance Of Mitochondrial Ca 2+ Uptake In mentioning

confidence: 99%

Sarcoplasmic Reticulum-Mitochondria Kissing in Cardiomyocytes: Ca2+, ATP, and Undisclosed Secrets

Rossini

Filadi

2020

Front. Cell Dev. Biol.

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In cardiomyocytes, to carry out cell contraction, the distribution, morphology, and dynamic interaction of different cellular organelles are tightly regulated. For instance, the repetitive close apposition between junctional sarcoplasmic reticulum (jSR) and specialized sarcolemma invaginations, called transverse-tubules (TTs), is essential for an efficient excitation-contraction coupling (ECC). Upon an action potential, Ca 2+ microdomains, generated in synchrony at the interface between TTs and jSR, underlie the prompt increase in cytosolic Ca 2+ concentration, ultimately responsible for cell contraction during systole. This process requires a considerable amount of energy and the active participation of mitochondria, which encompass ∼30% of the cell volume and represent the major source of ATP in the heart. Importantly, in adult cardiomyocytes, mitochondria are distributed in a highly orderly fashion and strategically juxtaposed with SR. By taking advantage of the vicinity to Ca 2+ releasing sites, they take up Ca 2+ and modulate ATP synthesis according to the specific cardiac workload. Interestingly, with respect to SR, a biased, polarized positioning of mitochondrial Ca 2+ uptake/efflux machineries has been reported, hinting the importance of a strictly regulated mitochondrial Ca 2+ handling for heart activity. This notion, however, has been questioned by the observation that, in some mouse models, the deficiency of specific molecules, modulating mitochondrial Ca 2+ dynamics, triggers non-obvious cardiac phenotypes. This review will briefly summarize the physiological significance of SRmitochondria apposition in cardiomyocytes, as well as the pathological consequences of an altered organelle communication, focusing on Ca 2+ signaling. We will discuss ongoing debates and propose future research directions.

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“…A recent report indicates that mitochondria AKAPs are arranged into specialized membrane microdomains and this physical interaction places PKA proximal to mitochondrial substrates such as Bad. 248 These microdomain associations are greatly influenced by local phosphatases capable of influencing the stability of PKA signaling on the OMM. Recently, post-translational modification of AKAP-1 has been shown to affect protein stability on the OMM as well.…”

Section: A-kinase Anchoring Protein 1 (Akap-1)mentioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

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Phosphatases control PKA-dependent functional microdomains at the outer mitochondrial membrane

Cited by 43 publications

References 54 publications

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

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

Sarcoplasmic Reticulum-Mitochondria Kissing in Cardiomyocytes: Ca2+, ATP, and Undisclosed Secrets

Phosphoregulation on mitochondria: Integration of cell and organelle responses

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