Regulation of Mitochondrial Homeostasis by sAC-Derived cAMP Pool: Basic and Translational Aspects

Aslam, Muhammad; Ladilov, Yury

doi:10.3390/cells10020473

Cited by 7 publications

(12 citation statements)

References 102 publications

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“…Numerous studies argue for the key role of the cAMP signaling in mitochondrial biology and homeostasis [ 72 , 73 ]. However, only a few reports have linked cAMP signaling to the regulation of mitochondrial homeostasis by AMPK.…”

Section: Functional and Translational Significance Of The Camp/ampk Axismentioning

confidence: 99%

Emerging Role of cAMP/AMPK Signaling

Aslam

Ladilov

2022

Cells

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114

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The 5′-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a natural energy sensor in mammalian cells that plays a key role in cellular and systemic energy homeostasis. At the cellular level, AMPK supports numerous processes required for energy and redox homeostasis, including mitochondrial biogenesis, autophagy, and glucose and lipid metabolism. Thus, understanding the pathways regulating AMPK activity is crucial for developing strategies to treat metabolic disorders. Mounting evidence suggests the presence of a link between cyclic AMP (cAMP) and AMPK signaling. cAMP signaling is known to be activated in circumstances of physiological and metabolic stress due to the release of stress hormones, such as adrenaline and glucagon, which is followed by activation of membrane-bound adenylyl cyclase and elevation of cellular cAMP. Because the majority of physiological stresses are associated with elevated energy consumption, it is not surprising that activation of cAMP signaling may promote AMPK activity. Aside from the physiological role of the cAMP/AMPK axis, numerous reports have suggested its role in several pathologies, including inflammation, ischemia, diabetes, obesity, and aging. Furthermore, novel reports have provided more mechanistic insight into the regulation of the cAMP/AMPK axis. In particular, the role of distinct cAMP microdomains generated by soluble adenylyl cyclase in regulating basal and induced AMPK activity has recently been demonstrated. In the present review, we discuss current advances in the understanding of the regulation of the cAMP/AMPK axis and its role in cellular homeostasis and explore some translational aspects.

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Section: Functional and Translational Significance Of The Camp/ampk Axismentioning

confidence: 99%

Emerging Role of cAMP/AMPK Signaling

Aslam

Ladilov

2022

Cells

Self Cite

114

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“…It has been suggested that sAC, as an intracellular pH and metabolic sensor, may play role in a tumorigenesis, since cellular pH and metabolism strongly correlate to tumor proliferation and metastatic spread [ 117 ] Studies have shown that sAC expression is diminished in many solid and hematologic human cancers, including embryonic carcinoma, teratoma, seminoma, yolk sac tumor, some types of leukemia, and others [ 118 ]. Preliminary data on animal and cell line models demonstrated that loss of sAC activity enhances cellular transformation in vitro, activates the MAP kinase signaling pathway, and induces tumorigenesis [ 118 , 119 ]. However, to our knowledge, reports regarding sAC involvement in OC development are missing.…”

Section: Signal Transduction Pathways As Potential Therapeutic Targetsmentioning

confidence: 99%

cAMP-Dependent Signaling and Ovarian Cancer

Kilanowska

Ziółkowska

Stasiak

et al. 2022

Cells

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cAMP-dependent pathway is one of the most significant signaling cascades in healthy and neoplastic ovarian cells. Working through its major effector proteins—PKA and EPAC—it regulates gene expression and many cellular functions. PKA promotes the phosphorylation of cAMP response element-binding protein (CREB) which mediates gene transcription, cell migration, mitochondrial homeostasis, cell proliferation, and death. EPAC, on the other hand, is involved in cell adhesion, binding, differentiation, and interaction between cell junctions. Ovarian cancer growth and metabolism largely depend on changes in the signal processing of the cAMP-PKA-CREB axis, often associated with neoplastic transformation, metastasis, proliferation, and inhibition of apoptosis. In addition, the intracellular level of cAMP also determines the course of other pathways including AKT, ERK, MAPK, and mTOR, that are hypo- or hyperactivated among patients with ovarian neoplasm. With this review, we summarize the current findings on cAMP signaling in the ovary and its association with carcinogenesis, multiplication, metastasis, and survival of cancer cells. Additionally, we indicate that targeting particular stages of cAMP-dependent processes might provide promising therapeutic opportunities for the effective management of patients with ovarian cancer.

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“…Impairment of OXPHOS dysfunction is linked to patients with primary open-angle glaucoma 31 and there is supporting evidence indicating that OXPHOS serves as the primary location for the production of mitochondrial superoxide in the presence of PQ 19 . Because the sAC/cAMP pathway is associated with mitochondrial biogenesis and OXPHOS function 10, 12, 32, 33, 34 , we next examined whether sAC activation promotes expression levels of PGC-1α and mitochondrial transcription factor A (TFAM) proteins, and OXPHOS complexes in the retina affected by oxidative stress. We found that oxidative stress significantly decreased PGC-1α and TFAM protein expression in the retina (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Hence, our findings emphasize a critical role of the sAC/cAMP/PKA signaling axis in mitochondrial protection in RGCs. Activation of cAMP signaling is crucial in mitochondrial biogenesis in mammalian cells 40, 50 and a deficiency of sAC has been linked to impaired OXPHOS activity 12 . Hence, our findings suggest that the sAC/cAMP/PKA-mediated modulation of mitochondrial biogenesis could protect RGCs by enhancing OXPHOS activity in response to oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…Current evidence indicates that the sAC/cAMP/PKA signaling pathway is linked to mitochondrial protection, ultimately promoting cell survival in neurons, notably in RGCs 10, 11 . The sAC modulates the cAMP activity within the mitochondrial matrix 12, 13 , and two mitochondrial cAMP pools influenced by sAC are associated with the outer mitochondrial membrane and the intermembrane space of mitochondria 14, 15 . Considering that the activation of the sAC-mediated cAMP/PKA signaling pathway is crucial for boosting the survival of RGCs and promoting axon growth 11, 16 , RGC protection from elevated IOP and oxidative stress could serve as a therapeutic approach in addressing glaucomatous neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

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Activating soluble adenylyl cyclase protects mitochondria, rescues retinal ganglion cells, and ameliorates visual dysfunction caused by oxidative stress

Bastola,

Perkins,

Huu

et al. 2024

Preprint

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Oxidative stress is a key factor causing mitochondrial dysfunction and retinal ganglion cell (RGC) death in glaucomatous neurodegeneration. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway is involved in mitochondrial protection, promoting RGC survival. Soluble adenylyl cyclase (sAC) is one of the key regulators of the cAMP/PKA signaling pathway. However, the precise molecular mechanisms underlying the sAC-mediated signaling pathway and mitochondrial protection in RGCs that counter oxidative stress are not well characterized. Here, we demonstrate that sAC plays a critical role in protecting RGC mitochondria from oxidative stress. Using mouse models of oxidative stress, we found that activating sAC protected RGCs, blocked AMP-activated protein kinase activation, inhibited glial activation, and improved visual function. Moreover, we found that this is the result of preserving mitochondrial dynamics (fusion and fission), promoting mitochondrial bioenergetics and biogenesis, and preventing metabolic stress and apoptotic cell death in a paraquat oxidative stress model. Notably, sAC activation ameliorated mitochondrial dysfunction in RGCs by enhancing mitochondrial biogenesis, preserving mitochondrial structure, and increasing ATP production in oxidatively stressed RGCs. These findings suggest that activating sAC enhances the mitochondrial structure and function in RGCs to counter oxidative stress, consequently promoting RGC protection. We propose that modulation of the sAC-mediated signaling pathway has therapeutic potential acting on RGC mitochondria for treating glaucoma and other retinal diseases.

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Regulation of Mitochondrial Homeostasis by sAC-Derived cAMP Pool: Basic and Translational Aspects

Cited by 7 publications

References 102 publications

Emerging Role of cAMP/AMPK Signaling

Emerging Role of cAMP/AMPK Signaling

cAMP-Dependent Signaling and Ovarian Cancer

Activating soluble adenylyl cyclase protects mitochondria, rescues retinal ganglion cells, and ameliorates visual dysfunction caused by oxidative stress

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