Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer

Xiong, Xin; Hasani, Sumati; Young, Lyndsay E.A.; Rivas, Dylan R.; Skaggs, Ashley T.; Martínez, Rebecca; Wang, Chi; Weiss, Heidi L.; Gentry, Matthew S.; Sun, Ramon C.; Gao, Tianyan

doi:10.1038/s41418-022-00974-5

Cited by 38 publications

(32 citation statements)

References 50 publications

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“…Interestingly, we could demonstrate secretion of the modified DRP-1 forms to the media and inter-cellular transfer of the pDRP-1 (S616) deposits from one astrocyte to another via TNTs and thicker protrusions. In line with our findings, a recent study suggests an integral role of DRP-1 in fatty acid β oxidation [ 40 ]. The authors demonstrated that DRP-1 knock-out cell line translocate LDs to their mitochondria, but have a decreased fatty acid degradation.…”

Section: Discussionsupporting

confidence: 93%

Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism

Zyśk

Beretta

Naia

et al. 2023

J Neuroinflammation

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Background Astrocytes play a central role in maintaining brain energy metabolism, but are also tightly connected to the pathogenesis of Alzheimer’s disease (AD). Our previous studies demonstrate that inflammatory astrocytes accumulate large amounts of aggregated amyloid-beta (Aβ). However, in which way these Aβ deposits influence their energy production remain unclear. Methods The aim of the present study was to investigate how Aβ pathology in astrocytes affects their mitochondria functionality and overall energy metabolism. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ42 fibrils for 7 days and analyzed over time using different experimental approaches. Results Our results show that to maintain stable energy production, the astrocytes initially increased their mitochondrial fusion, but eventually the Aβ-mediated stress led to abnormal mitochondrial swelling and excessive fission. Moreover, we detected increased levels of phosphorylated DRP-1 in the Aβ-exposed astrocytes, which co-localized with lipid droplets. Analysis of ATP levels, when blocking certain stages of the energy pathways, indicated a metabolic shift to peroxisomal-based fatty acid β-oxidation and glycolysis. Conclusions Taken together, our data conclude that Aβ pathology profoundly affects human astrocytes and changes their entire energy metabolism, which could result in disturbed brain homeostasis and aggravated disease progression.

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Section: Discussionsupporting

confidence: 93%

Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism

Zyśk

Beretta

Naia

et al. 2023

J Neuroinflammation

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“…Zhang et al [ 86 ] demonstrated that the Wnt/β-Catenin signaling pathway was promoted by Ribonuclease H1 antisense RNA 1 in lung cancer tissue and in non-small cell lung cancer (NSCLC) cell lines. In addition, PT130 cells and tumor organoid culture studies assumed that activation of dynamin-related protein 1 (Drp1) promotes fatty acid-induced metabolic reprogramming to enhance Wnt signaling in colon cancer [ 87 ]. Recently, Sana et al [ 88 ] were able to show that vitamin deficiency as well as the expression of VDR and retinoid X receptor (RXR) correlated with blood cancer diagnosis in patients.…”

Section: Discussionmentioning

confidence: 99%

Vitamin A- and D-Deficient Diets Disrupt Intestinal Antimicrobial Peptide Defense Involving Wnt and STAT5 Signaling Pathways in Mice

et al. 2023

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Vitamin A and D deficiencies are associated with immune modulatory effects and intestinal barrier impairment. However, the underlying mechanisms remain unclear. C57BL/6J mice were fed either a diet lacking in vitamin A (VAd), vitamin D (VDd) or a control diet (CD) for 12 weeks. Gut barrier function, antimicrobial peptide (AMP) defense and regulatory pathways were assessed. VAd mice compared to CD mice showed a reduced villus length in the ileum (p < 0.01) and decreased crypt depth in the colon (p < 0.05). In both VAd- and VDd-fed mice, ileal α-defensin 5 (p < 0.05/p < 0.0001 for VAd/VDd) and lysozyme protein levels (p < 0.001/p < 0.0001) were decreased. Moreover, mRNA expression of lysozyme (p < 0.05/p < 0.05) and total cryptdins (p < 0.001/p < 0.01) were reduced compared to controls. Furthermore, matrix metalloproteinase-7 (Mmp7) mRNA (p < 0.0001/p < 0.001) as well as components of the Wnt signaling pathway were decreased. VAd- and VDd-fed mice, compared to control mice, exhibited increased expression of pro-inflammatory markers and β-defensins in the colon. Organoid cell culture confirmed that vitamins A and D regulate AMP expression, likely through the Jak/STAT5 signaling pathway. In conclusion, our data show that vitamin A and D regulate intestinal antimicrobial peptide defense through Wnt and STAT5 signaling pathways.

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“…Activated Drp1 changes the metabolic pathway, facilitates the oxidation of fatty acids, and promotes the proliferation of colon cancer cells. 176 …”

Section: Phosphorylationmentioning

confidence: 99%

“…The kinase ERK catalyzes Drp1 phosphorylation at Ser616 to activate Drp1. Activated Drp1 changes the metabolic pathway, facilitates the oxidation of fatty acids, and promotes the proliferation of colon cancer cells 176 …”

Section: Phosphorylationmentioning

confidence: 99%

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

Zhong

Xiao

Xie

et al. 2023

MedComm

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Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on the backbones or amino acid side chains of proteins and expand the diversity of proteins, which provides the basis for the emergence of organismal complexity. To date, more than 650 types of protein modifications, such as the most well‐known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short‐chain and long‐chain acylation modifications, redox modifications, and irreversible modifications, have been described, and the inventory is still increasing. By changing the protein conformation, localization, activity, stability, charges, and interactions with other biomolecules, PTMs ultimately alter the phenotypes and biological processes of cells. The homeostasis of protein modifications is important to human health. Abnormal PTMs may cause changes in protein properties and loss of protein functions, which are closely related to the occurrence and development of various diseases. In this review, we systematically introduce the characteristics, regulatory mechanisms, and functions of various PTMs in health and diseases. In addition, the therapeutic prospects in various diseases by targeting PTMs and associated regulatory enzymes are also summarized. This work will deepen the understanding of protein modifications in health and diseases and promote the discovery of diagnostic and prognostic markers and drug targets for diseases.

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Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer

Cited by 38 publications

References 50 publications

Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism

Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism

Vitamin A- and D-Deficient Diets Disrupt Intestinal Antimicrobial Peptide Defense Involving Wnt and STAT5 Signaling Pathways in Mice

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

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