Mitochondrial cAMP-PKA signaling: What do we really know?

Amer, Yasmine Ould; Hébert-Chatelain, Étienne

doi:10.1016/j.bbabio.2018.04.005

Cited by 103 publications

(59 citation statements)

References 159 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Meanwhile, mitophagy is regulated by PINK1 and Parkin signaling . These processes are then coordinated via cell signaling events, such as those mediated by PKA, and crosstalk between signaling pathways . By generating an improved Gas7 ‐knockout mouse line, we found that Gas7 deficiency perturbs these homeostatic processes in neurons at multiple levels, resulting in the accumulation of elongated mitochondria within perinuclear clusters (Figure A).…”

Section: Discussionmentioning

confidence: 95%

Gas7 knockout affects PINK1 expression and mitochondrial dynamics in mouse cortical neurons

et al. 2020

View full text Add to dashboard Cite

Dynamic fission and fusion events regulate mitochondrial shape, distribution, and rejuvenation, and proper control of these processes is essential for neuronal homeostasis. Here, we report that Gas7, a known cytoskeleton regulator, controls mitochondrial dynamics within neurons of the central nervous system. In this study, we generated an improved Gas7‐knockout mouse and evaluated its mitochondrial phenotype. We first identified Gas7 in mitochondrial fractions from wild‐type brain tissue, and observed Gas7 colocalization with mitochondria in primary cortical neurons. In Gas7‐deficient brain tissue and neuronal cultures mitochondria were elongated with perinuclear clustering. These morphological abnormalities were associated with increased levels mitochondrial fusion proteins and increased PKA‐dependent phosphorylation of Drp‐1 in brain tissues, suggesting an imbalance of mitochondrial fusion and fission. Moreover, expression of mitochondrial quality control kinase, PINK1, and PINK1‐specific phosphorylation of Mfn‐2 (S442), Parkin (S65), and ubiquitin (S65) were all reduced in the knockout cells. Ectopic expression of Gas7 restored mitochondrial morphology and distribution, as well as PINK1 expression in Gas7‐null cortical neurons. Collectively, our results introduce a novel role of mouse Gas7 in determining the dynamics, morphology, and intracellular distribution of neuronal mitochondria, which are expected to be required for normal neuronal function.

show abstract

Section: Discussionmentioning

confidence: 95%

Gas7 knockout affects PINK1 expression and mitochondrial dynamics in mouse cortical neurons

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Mitochondrial PKA has long been associated with mitochondria through its interaction with scaffold proteins of the A‐kinase anchoring proteins (AKAP) family in particularly AKAP‐1 (or D‐AKAP as often used for the mitochondrial PKA scaffold) . PKA has been documented to affect numerous mitochondrial proteins ranging from bioenergetics to dynamics to redox homeostasis and cell survival . The substrates for mitochondrial PKA have been identified both on and within mitochondria suggesting the ability of mitochondrial PKA to transcend the OMM.…”

Section: Protein Kinase a G C (Agc Kinases)mentioning

confidence: 99%

“…Increasing the levels of mitochondrial PKA either through increasing AKAP‐1, targeting PKA to mitochondria, or pharmacological activation of PKA can offset mitochondrial dysfunction and neuronal cell death in PD models, in particular, those with PINK1 deficiency . Similar to PD, dysregulation of PKA signaling has been noted in AD and models with elevated amyloid beta . Defects in mitochondrial health and trafficking in AD‐like conditions were alleviated by the reintroduction of PKA .…”

Section: Protein Kinase a G C (Agc Kinases)mentioning

confidence: 99%

“…Similar to PD, dysregulation of PKA signaling has been noted in AD and models with elevated amyloid beta . Defects in mitochondrial health and trafficking in AD‐like conditions were alleviated by the reintroduction of PKA . These results indicate that diminished PKA signaling is a component of neurodegenerative disorders and restoring local PKA activity could be a means to impede the pathogenesis of these conditions.…”

Section: Protein Kinase a G C (Agc Kinases)mentioning

confidence: 99%

See 1 more Smart Citation

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

View full text Add to dashboard Cite

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.

show abstract

“…Levels of cAMP inside oocytes can be increased after treatment with MAM reagents (Ramos Leal et al, 2018). A high level of cAMP in the cytoplasm may lead to a corresponding increase in the mitochondrial matrix, which, in turn, affects mitochondrial function (Di Benedetto, Gerbino, & Lefkimmiatis, 2018; Ould Amer & Hebert‐Chatelain, 2018). ATP levels will increase by mitochondrial redistribution and translocation, which transiently alter their local density within the ooplasm (Van Blerkom & Runner, 1984; Yu, Dumollard, Rossbach, Lai, & Swann, 2010).…”

Section: Discussionmentioning

confidence: 99%

Combined use of dbcAMP and IBMX minimizes the damage induced by a long‐term artificial meiotic arrest in mouse germinal vesicle oocytes

Han

Hao

et al. 2020

Molecular Reproduction Devel

View full text Add to dashboard Cite

Phosphodiesterase (PDE)‐mediated reduction of cyclic adenosine monophosphate (cAMP) activity can initiate germinal vesicle (GV) breakdown in mammalian oocytes. It is crucial to maintain oocytes at the GV stage for a long period to analyze meiotic resumption in vitro. Meiotic resumption can be reversibly inhibited in isolated oocytes by cAMP modulator forskolin, cAMP analog dibutyryl cAMP (dbcAMP), or PDE inhibitors, milrinone (Mil), Cilostazol (CLZ), and 3‐isobutyl‐1‐methylxanthine (IBMX). However, these chemicals negatively affect oocyte development and maturation when used independently. Here, we used ICR mice to develop a model that could maintain GV‐stage arrest with minimal toxic effects on subsequent oocyte and embryonic development. We identified optimal concentrations of forskolin, dbcAMP, Mil, CLZ, IBMX, and their combinations for inhibiting oocyte meiotic resumption. Adverse effects were assessed according to subsequent development potential, including meiotic resumption after washout, first polar body extrusion, early apoptosis, double‐strand DNA breaks, mitochondrial distribution, adenosine triphosphate levels, and embryonic development. Incubation with a combination of 50.0 μM dbcAMP and 10.0 μM IBMX efficiently inhibited meiotic resumption in GV‐stage oocytes, with low toxicity on subsequent oocyte maturation and embryonic development. This work proposes a novel method with reduced toxicity to effectively arrest and maintain mouse oocytes at the GV stage.

show abstract

Mitochondrial cAMP-PKA signaling: What do we really know?

Cited by 103 publications

References 159 publications

Gas7 knockout affects PINK1 expression and mitochondrial dynamics in mouse cortical neurons

Gas7 knockout affects PINK1 expression and mitochondrial dynamics in mouse cortical neurons

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Combined use of dbcAMP and IBMX minimizes the damage induced by a long‐term artificial meiotic arrest in mouse germinal vesicle oocytes

Contact Info

Product

Resources

About