Shengmai Formula suppressed over-activated Ras/MAPK pathway in C. elegans by opening mitochondrial permeability transition pore via regulating cyclophilin D

Liu, Yan; Zhi, Dejuan; Li, Menghui; Liu, Dongling; Wang, Xin; Wu, Zhengrong; Zhang, Zhan‐Xin; Fei, Dong‐Qing; Li, Yang; Zhu, Hongmei; Xie, Qing-Jian; Yang, Hui; Li, Hongyu

doi:10.1038/srep38934

Cited by 11 publications

(6 citation statements)

References 60 publications

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“…We used NAC at 9 mM, a concentration that has been shown to lower ROS [55] but has no effect on wild type viability [52]. Like other studies using prooxidants on let-60rasgf mutants [28], we found that although PQ had no effect on vulva formation in the wild type, it partially suppressed the Muv phenotype of let-60rasgf ( Fig 1D). Conversely, we found that NAC treatment had no effect on the wild type but enhanced the Muv phenotype of let-60rasgf ( Fig 1D).…”

Section: Ras Signalling Is Sensitive To Rossupporting

confidence: 60%

“…One of the ways ROS can participate in signalling, is by modulating the activities of small GTPases. For examples, the Ras signalling pathway is known to be modulated by ROS in mammals [26,27] and C. elegans [4,28]. One of the ways the RAS pathway is affected by ROS in mammals is by direct oxidation of a sensitive cysteine (C118) of the RAS protein itself, by nitric oxide (NO) and superoxide [29,30] as well as by hydrogen peroxide in the presence of transition metals [31].…”

Section: •-mentioning

confidence: 99%

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ROS regulation of RAS and vulva development in Caenorhabditis elegans

et al. 2020

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Reactive oxygen species (ROS) are signalling molecules whose study in intact organisms has been hampered by their potential toxicity. This has prevented a full understanding of their role in organismal processes such as development, aging and disease. In Caenorhabditis elegans, the development of the vulva is regulated by a signalling cascade that includes LET-60ras (homologue of mammalian Ras), MPK-1 (ERK1/2) and LIN-1 (an ETS transcription factor). We show that both mitochondrial and cytoplasmic ROS act on a gain-of-function (gf) mutant of the LET-60ras protein through a redox-sensitive cysteine (C118) previously identified in mammals. We show that the prooxidant paraquat as well as isp-1, nuo-6 and sod-2 mutants, which increase mitochondrial ROS, inhibit the activity of LET-60rasgf on vulval development. In contrast, the antioxidant NAC and loss of sod-1, both of which decrease cytoplasmic H 2 0 2 , enhance the activity of LET-60rasgf. CRISPR replacement of C118 with a non-oxidizable serine (C118S) stimulates LET-60rasgf activity, whereas replacement of C118 with aspartate (C118D), which mimics a strongly oxidised cysteine, inhibits LET-60rasgf. These data strongly suggest that C118 is oxidized by cytoplasmic H 2 0 2 generated from dismutation of mitochondrial and/or cytoplasmic superoxide, and that this oxidation inhibits LET-60ras. This contrasts with results in cultured mammalian cells where it is mostly nitric oxide, which is not found in worms, that oxidizes C118 and activates Ras. Interestingly, PQ, NAC and the C118S mutation do not act on the phosphorylation of MPK-1, suggesting that oxidation of LET-60ras acts on an as yet uncharacterized MPK-1-independent pathway. We also show that elevated cytoplasmic superoxide promotes vulva formation independently of C118 of LET-60ras and downstream of LIN-1. Finally, we uncover a role for the NADPH oxidases (BLI-3 and DUOX-2) and their redox-sensitive activator CED-10rac in stimulating vulva development. Thus, there are at least three genetically separable pathways by which ROS regulates vulval development.

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Section: Ras Signalling Is Sensitive To Rossupporting

confidence: 60%

Section: •-mentioning

confidence: 99%

ROS regulation of RAS and vulva development in Caenorhabditis elegans

et al. 2020

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“…MAPK activation promotes cancer progression and resistance to chemotherapeutic drugs [30,31]. On the contrary, inhibition of MAPK pathway inhibits tumor metastasis and tumor-related angiogenesis [32,33]. However, studies of MAPK pathway in EC have rarely been reported.…”

Section: Discussionmentioning

confidence: 99%

Knocking down of LINC01220 inhibits proliferation and induces apoptosis of endometrial carcinoma through silencing MAPK11

Yong

Kong

et al. 2019

Bioscience Reports

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Background: Endometrial carcinoma (EC) still threatens the health of women. Thus, to explore how long intergenic non-protein coding RNA 01220 regulates the development of EC. Methods: Whole genome expression profile data of EC and paracancerous tissues in TCGA database were downloaded. LINC01220 expression in EC and paracancerous tissues of patients in our hospital were detected by qRT-PCR. Furthermore, the relationship between LINC01220 expression and clinicopathological features of EC patients was analyzed. After transfection with sh-LINC01220 and pcDNA-MAPK11 (mitogen-activated protein kinase) in EC cells, proliferative, colony formation abilities and apoptosis were determined by cell counting kit-8 (CCK-8), colony formation assay and flow cytometry, respectively. Western blot was conducted to determine the regulatory role of LINC01220 on MAPK11. Results: TCGA data showed that LINC01220 expression is markedly higher in EC tissues than that of paracancerous tissues, which was consistent without detection in EC patients of our hospital. LINC01220 expression was positively correlated to pathological grade and International Federation of Gynecology and Obstetrics (FIGO) stage of EC patients. After knockdown of LINC01220 in EC cells, proliferative and colony formation abilities decreased, whereas apoptotic rate increased. Cor function analysis revealed the positive correlation between LINC01220 and MAPK11 in EC. MAPK11 expression was regulated by LINC01220 in EC cells. Overexpression of MAPK11 can reverse the tumor suppressing effect of LINC01220 on EC. Conclusions: LINC01220 promotes EC development by stimulating proliferation and inhibiting apoptosis of EC cells through up-regulating MAPK11.

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“…The mPTP activity mainly appeared as a property of mammalian and yeast mitochondria, where it was intensively investigated. However recently the mPTP was also reported in mussel [ 183 ], in sea urchin oocytes [ 184 ], in the nematode Caenorhabditis elegans [ 185 ], in plathelminths [ 186 ] and insects [ 187 , 188 ], while it is still controversial in crustaceans [ 189 , 190 ]. Indeed, it is not a “vertebrate invention” to rule cell fate, as initially thought [ 191 ].…”

Section: Overview Of the F 1 F O mentioning

confidence: 99%

Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology

Nesci

Trombetti

Pagliarani

et al. 2021

Life

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Under aerobic conditions, mitochondrial oxidative phosphorylation (OXPHOS) converts the energy released by nutrient oxidation into ATP, the currency of living organisms. The whole biochemical machinery is hosted by the inner mitochondrial membrane (mtIM) where the protonmotive force built by respiratory complexes, dynamically assembled as super-complexes, allows the F1FO-ATP synthase to make ATP from ADP + Pi. Recently mitochondria emerged not only as cell powerhouses, but also as signaling hubs by way of reactive oxygen species (ROS) production. However, when ROS removal systems and/or OXPHOS constituents are defective, the physiological ROS generation can cause ROS imbalance and oxidative stress, which in turn damages cell components. Moreover, the morphology of mitochondria rules cell fate and the formation of the mitochondrial permeability transition pore in the mtIM, which, most likely with the F1FO-ATP synthase contribution, permeabilizes mitochondria and leads to cell death. As the multiple mitochondrial functions are mutually interconnected, changes in protein composition by mutations or in supercomplex assembly and/or in membrane structures often generate a dysfunctional cascade and lead to life-incompatible diseases or severe syndromes. The known structural/functional changes in mitochondrial proteins and structures, which impact mitochondrial bioenergetics because of an impaired or defective energy transduction system, here reviewed, constitute the main biochemical damage in a variety of genetic and age-related diseases.

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Shengmai Formula suppressed over-activated Ras/MAPK pathway in C. elegans by opening mitochondrial permeability transition pore via regulating cyclophilin D

Cited by 11 publications

References 60 publications

ROS regulation of RAS and vulva development in Caenorhabditis elegans

ROS regulation of RAS and vulva development in Caenorhabditis elegans

Knocking down of LINC01220 inhibits proliferation and induces apoptosis of endometrial carcinoma through silencing MAPK11

Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology

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