Impaired oxygen-sensitive regulation of mitochondrial biogenesis within the von Hippel–Lindau syndrome

Li, Shuijie; Li, Wenyu; Yuan, Jing; Bullova, Petra; Wu, Jing‐Ming; Zhang, Xuepei; Liu, Yong; Plescher, M.; Rodríguez, Javier; Bedoya-Reina, Oscar C.; Jannig, Paulo R.; Valente-Silva, Paula; Yu, Meng; Henriksson, Marie Arsenian; Zubarev, Roman A.; Smed‐Sörensen, Anna; Suzuki, Carolyn K.; Ruas, Jorge L.; Holmberg, Johan; Juhlin, C. Christofer; Kriegsheim, Alex von; Cao, Yihai; Schlisio, Susanne

doi:10.1038/s42255-022-00593-x

Cited by 11 publications

(13 citation statements)

References 52 publications

(67 reference statements)

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“…TFAM can maintain the stability of mtDNA. As the hydrolase of TFAM, LONP1 (Lon peptidase 1) can reduce the occurrence of ferroptosis when the LONP1-TFAM pathway is inhibited (Li, Zhang, Liu, Kang, Klionsky & Tang, 2021;Li et al, 2022a). In our experiment, we find that the primary cells of ksp-cre TFAM flox/flox mice are more sensitive to ferroptosis compared with TFAM flox/flox mice.…”

Section: Discussionmentioning

confidence: 55%

Myricanol represses renal fibrosis by activating tubular TFAM-ZNRF1/LCN2 pathway to improve mitochondrial bioenergetics

Zheng

You

Bao

et al. 2023

Preprint

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Background: Mitochondrial biology destroy lead to renal fibrosis. Targeted therapy of ferroptosis may play an important role in protecting renal functions. Myricanol has been shown ameliorate muscle dysfunction by increasing mitochondrial biogenesis. However, few studies on myricanol in renal fibrosis has been performed. Purpose: We explore that myricanol can relieve renal fibrosis by improving mitochondrial bioenergy and inhibiting ferroptosis. Approach: Renal ferroptosis model was established using bilateral ischemia reperfusion (BIRI), which was used to study association between ferroptosis and renal fibrosis. Ferroptosis associated protein including zinc and ring finger 1 (ZNRF1) and iron transport-related protein lipocalin-2 (LCN2) interactions were verified by co-immunoprecipitation. Two concentrations of myricanol, namely 0.5 mg/kg and 2 mg/kg, were included to treat unilateral ureteral obstruction (UUO) induced mouse model of chronic kidney disease (CKD). Results: We have shown that myricanol could inhibits ferroptosis, maintains mitochondrial integrity and renal function. Mitochondrial copy number were decreased in CKD patient blood sample. We further confirmed that primary renal tubular cells with TFAM deficiency were more prone to ferroptosis. Transcriptional sequencing showed the level of ZNRF1 having significant differences between TFAM-/- and TFAM+/+ group. TFAM deficiency decrease the interaction between LCN2 and ZNRF1. Treatment with myricanol reduced renal fibrosis by regulating TFAM expression and ferroptosis. Conclusions: Our study firstly demonstrated that myricanol strengthen tubular bioenergetic capacity depended on TFAM increasing the interaction between LCN2 and ZNRF1 to inhibit ferroptosis and suggested that myricanol might be promising drugs for treating renal fibrosis.

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Section: Discussionmentioning

confidence: 55%

Myricanol represses renal fibrosis by activating tubular TFAM-ZNRF1/LCN2 pathway to improve mitochondrial bioenergetics

Zheng

You

Bao

et al. 2023

Preprint

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“…Moreover, HIF‐1α was significantly increased and concentrated in the nucleus to exert its function as a transcription factor and was positively correlated with the degree of gastric mucosal injury. Because mitochondria are strongly regulated by hypoxia, they sense O 2 concentrations and initiate cellular responses to hypoxia 34 . In response to hypoxia and the upregulation of HIF‐1α, mitochondria exhibit morphological abnormalities and functional impairment, leading to enhanced oxidative stress and ROS release in GC cells and injured gastric mucosal epithelial cells induced by PHT.…”

Section: Discussionmentioning

confidence: 99%

“…Because mitochondria are strongly regulated by hypoxia, they sense O 2 concentrations and initiate cellular responses to hypoxia. 34 In response to hypoxia and the upregulation of HIF‐1α, mitochondria exhibit morphological abnormalities and functional impairment, leading to enhanced oxidative stress and ROS release in GC cells and injured gastric mucosal epithelial cells induced by PHT.…”

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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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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“…By utilizing bioinformatics analysis techniques and conducting in vitro validation experiments, we have acquired the subsequent findings: (1) HIF-1α and CITED2 [ 25 ] exhibited significant expression levels in healthy human nucleus pulposus cells, whereas HIF-2α (EPAS1), CA9 [ 26 ], PPP1R15A [ 27 ], VEGFA [ 26 ], and EGLN3 [ 28 , 29 ] were observed to be upregulated in deteriorated nucleus pulposus cells. (2) HIF-2α, CA9, PPP1R15A, VEGFA, and EGLN3 tended to decrease to varying degrees in response to LPS + PT2399 loaded PP20.…”

Section: Discussionmentioning

confidence: 99%

Poly-3-hydroxybutyrate-co-3-hydroxyvalerate(PHBV)-Polyethylene glycol 20k(PEG20k) as a promising delivery system for PT2399 in the treatment of disc degeneration

Li,

Zhang,

Huang

et al. 2024

J Biol Eng

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Disc degeneration often leads to a highly prevalent symptom known as low back pain. Healthy nucleus pulposus tissue exhibited a hypoxic environment devoid of blood vessels, while degenerated nucleus pulposus experienced hypoxic deterioration and the formation of new blood vessels. In this study, the expression of important genes like HIF-2α was found to vary between normal and degenerated nucleus pulposus cells when compared to the hypoxic surroundings. The aim of this study was to examine how HIF-2α is controlled in nucleus pulposus cells under hypoxic conditions and its role in angiogenic mechanisms. To assess the impact of gradual inhibition of HIF-2α on disc degeneration, we utilized PHBV-based synthetic materials loaded with inhibitors of HIF-2α. Specifically, we employed LPS and PT2399 loaded PHBV-PEG20k (PP20) to intervene with human nucleus pulposus cells. Additionally, we treated APD rat models with PT2399 loaded PP20 to evaluate its effects. The expression levels of target markers in nucleus pulposus cells were detected using PCR, WB, and immunofluorescence. Additionally, the effect of drugs on disc degeneration was identified through HE staining. The findings indicated that HIF-2α, CAIX, PPP1R15A, VEGFA, and EGLN3 could potentially serve as new indicators of disc degeneration. Additionally, HIF-2α might contribute to the progression of disc degeneration through involvement in angiogenesis and the regulation of hypoxia. Furthermore, the utilization of PT2399 loaded PHBV-PEG20k (PP20) could potentially offer a fresh alternative for treating disc degeneration.

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Impaired oxygen-sensitive regulation of mitochondrial biogenesis within the von Hippel–Lindau syndrome

Cited by 11 publications

References 52 publications

Myricanol represses renal fibrosis by activating tubular TFAM-ZNRF1/LCN2 pathway to improve mitochondrial bioenergetics

Myricanol represses renal fibrosis by activating tubular TFAM-ZNRF1/LCN2 pathway to improve mitochondrial bioenergetics

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

Poly-3-hydroxybutyrate-co-3-hydroxyvalerate(PHBV)-Polyethylene glycol 20k(PEG20k) as a promising delivery system for PT2399 in the treatment of disc degeneration

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