BRCA1 Deficiency Impairs Mitophagy and Promotes Inflammasome Activation and Mammary Tumor Metastasis

Chen, Qiang; Lei, Josh Haipeng; Bao, Jiaolin; Wang, Haitao; Wu, Hao; Li, Licen; Peng, Cheng; Masuda, Takaaki; Kai, Masahiro; Xu, Jun; Xu, Xiaoling; Deng, Chu Xia

doi:10.1002/advs.201903616

Cited by 53 publications

(52 citation statements)

References 62 publications

(95 reference statements)

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“…This is consistent with a possible defect in mitochondrial fusion/fission in A-T cells. A recent report shows that BRCA1 deficiency results in a higher level of MFN1/2 protein expression, accelerating mitochondrial fusion, which can block the separation of damaged mitochondria from healthy ones and negatively affect mitophagy ( Chen et al., 2020 ). In addition, clearing damaged mitochondria is defective in Atm-deficient cells and increasing intracellular NAD+ is associated with improving mitochondrial quality via mitophagy ( Valentin-Vega et al., 2012 ; Fang et al., 2016 ).…”

Section: Resultsmentioning

confidence: 99%

Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia

et al. 2021

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There is evidence that ATM mutated in ataxia-telangiectasia (A-T) plays a key role in protecting against mitochondrial dysfunction, the mechanism for which remains unresolved. We demonstrate here that ATM-deficient cells are exquisitely sensitive to nutrient deprivation, which can be explained by defective cross talk between the endoplasmic reticulum (ER) and the mitochondrion. Tethering between these two organelles in response to stress was reduced in cells lacking ATM, and consistent with this, Ca 2+ release and transfer between ER and mitochondria was reduced dramatically when compared with control cells. The impact of this on mitochondrial function was evident from an increase in oxygen consumption rates and a defect in mitophagy in ATM-deficient cells. Our findings reveal that ER-mitochondrial connectivity through IP3R1-GRP75-VDAC1, to maintain Ca 2+ homeostasis, as well as an abnormality in mitochondrial fusion defective in response to nutrient stress, can account for at least part of the mitochondrial dysfunction observed in A-T cells.

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Section: Resultsmentioning

confidence: 99%

Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia

et al. 2021

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“…NF- κ B is essential for NLRP3 inflammasome activation, and the findings from us and other laboratories demonstrated that NF- κ B inhibition was sufficient to alleviate the activation of NLRP3 inflammasome [ 34 ]. Moreover, results from Chen et al revealed that AMPK α regulated dynamin-related protein 1-mediated mitochondrial fission and thereby restrained NLRP3 inflammasome activation [ 49 ]. Collectively, our data defined miR-31-5p as a promising therapeutic target for the treatment of ALI.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-31-5p Exacerbates Lipopolysaccharide-Induced Acute Lung Injury via Inactivating Cab39/AMPKα Pathway

Jiang

Zhao

Wen

et al. 2020

Oxidative Medicine and Cellular Longevity

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Acute lung injury (ALI) and the subsequent acute respiratory distress syndrome remain devastating diseases with high mortality rates and poor prognoses among patients in intensive care units. The present study is aimed at investigating the role and underlying mechanisms of microRNA-31-5p (miR-31-5p) on lipopolysaccharide- (LPS-) induced ALI. Mice were pretreated with miR-31-5p agomir, antagomir, and their negative controls at indicated doses for 3 consecutive days, and then they received a single intratracheal injection of LPS (5 mg/kg) for 12 h to induce ALI. MH-S murine alveolar macrophage cell lines were cultured to further verify the role of miR-31-5p in vitro. For AMP-activated protein kinase α (AMPKα) and calcium-binding protein 39 (Cab39) inhibition, compound C or lentiviral vectors were used in vivo and in vitro. We observed an upregulation of miR-31-5p in lung tissue upon LPS injection. miR-31-5p antagomir alleviated, while miR-31-5p agomir exacerbated LPS-induced inflammation, oxidative damage, and pulmonary dysfunction in vivo and in vitro. Mechanistically, miR-31-5p antagomir activated AMPKα to exert the protective effects that were abrogated by AMPKα inhibition. Further studies revealed that Cab39 was required for AMPKα activation and pulmonary protection by miR-31-5p antagomir. We provide the evidence that endogenous miR-31-5p is a key pathogenic factor for inflammation and oxidative damage during LPS-induced ALI, which is related to Cab39-dependent inhibition of AMPKα.

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“…Globular adiponectin has been shown to decrease BC cell growth as a result of NLRP3 inflammasome inhibition (82). An in vitro/in vivo study showed that BRCA1 deficit affected mitochondrial function, mitophagy and NLRP3 inflammasome activation, thus promoting metastasis (83). The findings of these studies provide evidence that inflammasome inhibition could serve as a therapeutic target for the treatment of BC.…”

Section: Inflammasomes and Bcmentioning

confidence: 91%

NLRP3 Inflammasome From Bench to Bedside: New Perspectives for Triple Negative Breast Cancer

et al. 2020

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The tumor microenvironment (TME) is crucial in cancer onset, progression and response to treatment. It is characterized by an intricate interaction of immune cells and cytokines involved in tumor development. Among these, inflammasomes are oligomeric molecular platforms and play a key role in inflammatory response and immunity. Inflammasome activation is initiated upon triggering of pattern recognition receptors (Toll-like receptors, NOD-like receptors, and Absent in melanoma like receptors), on the surface of immune cells with the recruitment of caspase-1 by an adaptor apoptosis-associated specklike protein. This structure leads to the activation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and participates in different biological processes exerting its effects. To date, the Nod-Like Receptor Protein 3 (NLRP3) inflammasome has been well studied and its involvement has been established in different cancer diseases. In this review, we discuss the structure, biology and mechanisms of inflammasomes with a special focus on the specific role of NLRP3 in breast cancer (BC) and in the subgroup of triple negative BC. The NLRP3 inflammasome and its downstream pathways could be considered novel potential tumor biomarkers and could open new frontiers in BC treatment.

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BRCA1 Deficiency Impairs Mitophagy and Promotes Inflammasome Activation and Mammary Tumor Metastasis

Cited by 53 publications

References 62 publications

Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia

Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia

MicroRNA-31-5p Exacerbates Lipopolysaccharide-Induced Acute Lung Injury via Inactivating Cab39/AMPKα Pathway

NLRP3 Inflammasome From Bench to Bedside: New Perspectives for Triple Negative Breast Cancer

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