How AMPK and PKA Interplay to Regulate Mitochondrial Function and Survival in Models of Ischemia and Diabetes

Zhang, Jingdian; Wang, Yumeng; Liu, Xiaofeng; Dagda, Ruben K.; Zhang, Ying

doi:10.1155/2017/4353510

Cited by 61 publications

(48 citation statements)

References 121 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that there was evidence of AMPK activation by increasing AMPK phosphorylation at Thr172 in the retina and optic nerve in glaucomatous DBA/2J mice 14,51 . Also, it has been proposed that AMPK uncouples PKA from D-AKAP1 (AKAP140/149 and other splice variants AKAP121, sAKAP84) to promote mitochondrial fission and mitophagy 52 . Furthermore, AMPK is associated with the regulation of Drp1 phosphorylation 53,54 .…”

Section: Discussionmentioning

confidence: 99%

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

et al. 2020

View full text Add to dashboard Cite

Impairment of mitochondrial structure and function is strongly linked to glaucoma pathogenesis. Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying mitochondrial fragmentation and metabolic stress in glaucoma are poorly understood. We demonstrate here that glaucomatous retinal ganglion cells (RGCs) show loss of A-kinase anchoring protein 1 (AKAP1), activation of calcineurin (CaN) and reduction of dynamin-related protein 1 (Drp1) phosphorylation at serine 637 (Ser637). These findings suggest that AKAP1-mediated phosphorylation of Drp1 at Ser637 has a critical role in RGC survival in glaucomatous neurodegeneration. Male mice lacking AKAP1 show increases in CaN and total Drp1 levels, as well as a decrease in Drp1 phosphorylation at Ser637 in the retina. Ultrastructural analysis of mitochondria shows that loss of AKAP1 triggers mitochondrial fragmentation and loss, as well as mitophagosome formation in RGCs. Loss of AKAP1 deregulates oxidative phosphorylation (OXPHOS) complexes (Cxs) by increasing CxII and decreasing CxIII-V, leading to metabolic and oxidative stress. Also, loss of AKAP1 decreases Akt phosphorylation at Serine 473 (Ser473) and threonine 308 (Thr308) and activates the Bim/Bax signaling pathway in the retina. These results suggest that loss of AKAP1 has a critical role in RGC dysfunction by decreasing Drp1 phosphorylation at Ser637, deregulating OXPHOS, decreasing Akt phosphorylation at Ser473 and Thr308, and activating the Bim/Bax pathway in glaucomatous neurodegeneration. Thus, we propose that overexpression of AKAP1 or modulation of Drp1 phosphorylation at Ser637 are potential therapeutic strategies for neuroprotective intervention in glaucoma and other mitochondria-related optic neuropathies.

show abstract

Section: Discussionmentioning

confidence: 99%

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…AMPK can also phosphorylate p53 at S15 [114], thereby potentiating its activity in enhancing mitochondrial metabolism. Furthermore, it is noteworthy that although cell type-dependently, AMPK [115], p53 [116] AKT [117], and mTOR [118] activation can trigger mitochondrial fusion which may also be a possible explanation for enhanced mitochondrial activity. Since PARP inhibition alone do not induce CPD formation, we must take into account that the PARPi-mediated changes in the non-irradiated cells are mediated by CPD-independent mechanisms either through autophagy induction and/or NAD + prevention.…”

Section: Discussionmentioning

confidence: 99%

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

Hegedűs

Boros

Fidrus

et al. 2019

Cancers

View full text Add to dashboard Cite

Keratinocytes provide the first line of defense of the human body against carcinogenic ultraviolet (UV) radiation. Acute and chronic UVB-mediated cellular responses were widely studied. However, little is known about the role of mitochondrial regulation in UVB-induced DNA damage. Here, we show that poly (ADP-ribose) polymerase 1 (PARP1) and ataxia-telangiectasia-mutated (ATM) kinase, two tumor suppressors, are important regulators in mitochondrial alterations induced by UVB. Our study demonstrates that PARP inhibition by ABT-888 upon UVB treatment exacerbated cyclobutane pyrimidine dimers (CPD) accumulation, cell cycle block and cell death and reduced cell proliferation in premalignant skin keratinocytes. Furthermore, in human keratinocytes UVB enhanced oxidative phosphorylation (OXPHOS) and autophagy which were further induced upon PARP inhibition. Immunoblot analysis showed that these cellular responses to PARP inhibition upon UVB irradiation strongly alter the phosphorylation level of ATM, adenosine monophosphate-activated kinase (AMPK), p53, protein kinase B (AKT), and mammalian target of rapamycin (mTOR) proteins. Furthermore, chemical inhibition of ATM led to significant reduction in AMPK, p53, AKT, and mTOR activation suggesting the central role of ATM in the UVB-mediated mitochondrial changes. Our results suggest a possible link between UVB-induced DNA damage and metabolic adaptations of mitochondria and reveal the OXPHOS-regulating role of autophagy which is dependent on key metabolic and DNA damage regulators downstream of PARP1 and ATM. IntroductionMitochondria regulate their shape, number, distribution, mass, content of mitochondrial DNA (mtDNA), and metabolic capacity in a process called mitochondrial biogenesis, which requires the orchestration of complex transcriptional control of both nuclear and mitochondrial genes [1,2]. The function of mitochondrial biogenesis is to provide quality control of mitochondria by regulating mitochondrial fission, fusion, and mitophagy [3,4] to maximize the energy utilization of mitochondria [5] to meet cellular and environmental demands. Imbalances or perturbations in these processes can lead to mitochondrial dysfunction [3,6].Accumulating evidence suggests that mitochondria also play a central role in skin physiology. Although, involvement of other organ systems predominates in classical mitochondrial disorders, several cutaneous diseases can be linked to mitochondrial dysfunctions [7]. Interestingly, mitochondria lack functional nucleotide excision repair (NER) pathway [8,9] which is responsible for the removal of ultraviolet (UV)-induced DNA lesions including cyclobutane pyrimidine dimers (CPD). Accumulation of these DNA photoproducts in mtDNA leads to mutations and deletions resulting in mitochondrial alterations which have been associated with photoaging [10,11] and are present in melanoma [12], as well as in non-melanoma skin cancers [13,14]. The other types of mitochondrial alterations such as upregulated oxidative phosphorylation (OXPHOS), mitochondrial memb...

show abstract

“…Mitochondrial fusion/mitophagy is related to AMPK, a key energy sensor that regulates cellular metabolism to maintain energy homeostasis [26,27]. Cui et al showed that melatonin treatment reduced the apoptosis of human umbilical vein endothelial cells by promoting mitochondrial fusion through activation of the AMPK pathway [13].…”

mentioning

confidence: 99%

Melatonin Attenuates Calcium Deposition from Vascular Smooth Muscle Cells by Activating Mitochondrial Fusion and Mitophagy via an AMPK/OPA1 Signaling Pathway

Chen

Zhou

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Mitochondrial fusion/mitophagy plays a role in cardiovascular calcification. Melatonin has been shown to protect against cardiovascular disease. This study sought to explore whether melatonin attenuates vascular calcification by regulating mitochondrial fusion/mitophagy via the AMP-activated protein kinase/optic atrophy 1 (AMPK/OPA1) signaling pathway. The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualized by Alizarin Red S staining, while calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure expression of runt-related transcription factor 2 (Runx2), mitofusin 2 (Mfn2), mito-light chain 3 (mito-LC3) II, and cleaved caspase 3. Melatonin markedly reduced calcium deposition and ALP activity. Runx2 and cleaved caspase 3 were downregulated in response to melatonin, whereas Mfn2 and mito-LC3II were enhanced and accompanied by decreased mitochondrial superoxide levels. Melatonin also maintained mitochondrial function and promoted mitochondrial fusion/mitophagy via the OPA1 pathway. However, OPA1 deletion abolished the protective effects of melatonin on VSMC calcification. Melatonin treatment significantly increased p-AMPK and OPA1 protein expression, whereas treatment with compound C ablated the observed benefits of melatonin treatment. Collectively, our results demonstrate that melatonin protects VSMCs against calcification by promoting mitochondrial fusion/mitophagy via the AMPK/OPA1 pathway.

show abstract

How AMPK and PKA Interplay to Regulate Mitochondrial Function and Survival in Models of Ischemia and Diabetes

Cited by 61 publications

References 121 publications

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

Melatonin Attenuates Calcium Deposition from Vascular Smooth Muscle Cells by Activating Mitochondrial Fusion and Mitophagy via an AMPK/OPA1 Signaling Pathway

Contact Info

Product

Resources

About