The HIF-1/ BNIP3 pathway mediates mitophagy to inhibit the pyroptosis of fibroblast-like synoviocytes in rheumatoid arthritis

Hong, Zhongyang; Wang, Han; Zhang, Tianjing; Xu, Li; Zhai, Yuanfang; Zhang, Xianzheng; Zhang, Feng; Zhang, Lingling

doi:10.1016/j.intimp.2023.111378

Cited by 2 publications

(2 citation statements)

References 65 publications

(44 reference statements)

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“…Consistent with our current results, HIF‐1α has been implicated in the regulation of inflammatory responses and cell death pathways, particularly NLRP3 inflammasome‐associated pyroptosis. 49 , 50 , 51 HIF‐1α appears to regulate the expression of NLRP3, and mitophagy can suppress pyroptosis by blocking the HIF‐1α/NLRP3 pathway under hypoxia. 50 miRNA‐18a inhibits HIF1‐α/NLRP3 signalling to hinder pyroptosis and impair osteogenic differentiation.…”

Section: Discussionmentioning

confidence: 99%

“… 49 , 50 , 51 HIF‐1α appears to regulate the expression of NLRP3, and mitophagy can suppress pyroptosis by blocking the HIF‐1α/NLRP3 pathway under hypoxia. 50 miRNA‐18a inhibits HIF1‐α/NLRP3 signalling to hinder pyroptosis and impair osteogenic differentiation. 51 HIF‐1α‐mediated glycolysis deficiency also alleviates NLRP3‐related inflammation, pyroptosis and oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

Xiao,

Liu,

Xie

et al. 2024

Clinical & Translational Med

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IntroductionHypoxia is an important characteristic of gastric mucosal diseases, and hypoxia‐inducible factor‐1α (HIF‐1α) contributes to microenvironment disturbance and metabolic spectrum abnormalities. However, the underlying mechanism of HIF‐1α and its association with mitochondrial dysfunction in gastric mucosal lesions under hypoxia have not been fully clarified.ObjectivesTo evaluate the effects of hypoxia‐induced HIF‐1α on the development of gastric mucosal lesions.MethodsPortal hypertensive gastropathy (PHG) and gastric cancer (GC) were selected as representative diseases of benign and malignant gastric lesions, respectively. Gastric tissues from patients diagnosed with the above diseases were collected. Portal hypertension (PHT)‐induced mouse models in METTL3 mutant or NLRP3‐deficient littermates were established, and nude mouse gastric graft tumour models with relevant inhibitors were generated. The mechanisms underlying hypoxic condition, mitochondrial dysfunction and metabolic alterations in gastric mucosal lesions were further analysed.ResultsHIF‐1α, which can mediate mitochondrial dysfunction via upregulation of METTL3/IGF2BP3‐dependent dynamin‐related protein 1 (Drp1) N6‐methyladenosine modification to increase mitochondrial reactive oxygen species (mtROS) production, was elevated under hypoxic conditions in human and mouse portal hypertensive gastric mucosa and GC tissues. While blocking HIF‐1α with PX‐478, inhibiting Drp1‐dependent mitochondrial fission via mitochondrial division inhibitor 1 (Mdivi‐1) treatment or METTL3 mutation alleviated this process. Furthermore, HIF‐1α influenced energy metabolism by enhancing glycolysis via lactate dehydrogenase A. In addition, HIF‐1α‐induced Drp1‐dependent mitochondrial fission also enhanced glycolysis. Drp1‐dependent mitochondrial fission and enhanced glycolysis were associated with alterations in antioxidant enzyme activity and dysfunction of the mitochondrial electron transport chain, resulting in massive mtROS production, which was needed for activation of NLRP3 inflammasome to aggravate the development of the PHG and GC.ConclusionsUnder hypoxic conditions, HIF‐1α enhances mitochondrial dysfunction via Drp1‐dependent mitochondrial fission and influences the metabolic profile by altering glycolysis to increase mtROS production, which can trigger NLRP3 inflammasome activation and mucosal microenvironment alterations to contribute to the development of benign and malignant gastric mucosal lesions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

Xiao,

Liu,

Xie

et al. 2024

Clinical & Translational Med

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Identification of stable reference genes for quantitative real-time PCR in human fibroblasts from lymph nodes and synovium

Rasouli,

van Ansenwoude,

Semmelink

et al. 2024

Preprint

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Real-time quantitative PCR (RT‒qPCR) has emerged as an accurate and widely used technique for measuring gene expression levels. However, its reliability depends on the selection of appropriate reference genes to normalize for sample input. Accordingly, the identification of reference genes characterized by stable expression in cells and conditions of interest is essential for ensuring accurate expression values. To date, no study has specifically identified suitable reference genes for primary human cultured fibroblast-like synoviocytes (FLS) and lymph node stromal cells (LNSCs) within the context of rheumatoid arthritis (RA). These stromal cells play a critical role in the pathogenesis of disease. In this study, we evaluated the suitability of 15 candidate reference genes for normalizing transcript expression in FLS and LNSCs subjected to various in vitro stimuli. We included traditional reference genes often used for transcript normalization in fibroblasts as well as candidate genes identified as suitable reference genes via GeneVestigator analysis of publicly available transcriptomic data. RefFinder algorithms were used to identify the most stable reference genes for transcript normalization across the cell types and different experimental conditions. We determined that the optimal number of reference genes for every experimental condition tested was two; RPLP0 and POLR2G exhibited the greatest stability across different experimental conditions for LNSCs. However, for FLS, we observed greater variability in the most stable reference genes across different experimental conditions. Although POLR2G and TBP emerged as the most stable reference genes under unstimulated conditions, our findings indicated that FLS require distinct reference genes for transcript normalization depending on the specific experimental conditions. Validation of the selected reference genes for normalizing the expression levels of metabolic genes in unstimulated FLS emphasized the importance of prior evaluation of potential reference genes, as arbitrary selection of reference genes could lead to data misinterpretation. This study constitutes the first systematic analysis for selecting optimal reference genes for transcript normalization in different types of human fibroblasts. Our findings emphasize the importance of proper selection of reference genes for each experimental condition separately when applying standard quantitative PCR technology for assessing gene expression levels.

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The HIF-1/ BNIP3 pathway mediates mitophagy to inhibit the pyroptosis of fibroblast-like synoviocytes in rheumatoid arthritis

Cited by 2 publications

References 65 publications

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

Identification of stable reference genes for quantitative real-time PCR in human fibroblasts from lymph nodes and synovium

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