Cr (VI) induced mitophagy via the interaction of HMGA2 and PARK2

Gao, Zeyun; Mei, Junjie; Yan, Xiaona; Jiang, Liping; Chen, Geng; Li, Qiujuan; Shi, Xiaoxia; Liu, Yong; Cao, Jun

doi:10.1016/j.toxlet.2020.08.012

Cited by 7 publications

(5 citation statements)

References 45 publications

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“…Though we previously demonstrated that Cr(VI) exerted the toxic effects of inducing premature senescence on L02 hepatocytes via the p53 signaling pathway [10], the underlying mechanism are not fully elucidated. Cr(VI), a highly toxic heavy metal, is broadly dispersed in the environment, which has various adverse effects on humans upon its exposure via inhalation, ingestion, and skin absorption especially pulmonary and liver injury [33,34]. There are series of studies on the role and underlying modulatory mechanisms of Cr(VI)-induced acute cytotoxicity in liver injury to date [13,35,36], but less attention has hitherto been drawn to the chronic cytotoxicity such as premature senescence.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cr(VI)-Induced Premature Senescence in L02 Hepatocytes by ROS-Ca2+-NF-κB Signaling

Zhang

Yang

Huang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Stress-induced premature senescence may be involved in the pathogeneses of acute liver injury. Hexavalent chromium [Cr(VI)], a common environmental pollutant related to liver injury, likely leads to premature senescence in L02 hepatocytes. However, the underlying mechanisms regarding hepatocyte premature senility in Cr(VI) exposure remain poorly understood. In this study, we found that chronic exposure of L02 hepatocytes to Cr(VI) led to premature senescence characterized by increased β-galactosidase activity, senescence-associated heterochromatin foci, G1 phase arrest, and decreased cell proliferation. Additionally, Cr(VI)-induced senescent L02 hepatocytes showed upregulated inflammation-related factors, such as IL-6 and fibroblast growth factor 23 (FGF23), which also exhibited reactive oxygen species (ROS) accumulation derived from mitochondria accompanied with increased concentration of intracellular calcium ions (Ca2+) and activity of nuclear factor kappa B (NF-κB). Of note is that ROS inhibition by N-acetyl-Lcysteine pretreatment not only alleviated Cr(VI)-induced premature senescence but also reduced the elevated intracellular Ca2+, activated NF-κB, and secretion of IL-6/FGF23. Intriguingly, the toxic effect of Cr(VI) upon premature senescence of L02 hepatocytes and increased levels of IL-6/FGF23 could be partially reversed by the intracellular Ca2+ chelator BAPTA-AM pretreatment. Furthermore, by utilizing the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that NF-κB mediated IL-6/FGF23 to regulate the Cr(VI)-induced L02 hepatocyte premature senescence, whilst the concentration of intracellular Ca2+ was not influenced by PDTC. To the best of our knowledge, our data reports for the first time the role of ROS-Ca2+-NF-κB signaling pathway in Cr(VI)-induced premature senescence. Our results collectively shed light on further exploration of innovative intervention strategies and treatment targeting Cr(VI)-induced chronic liver damage related to premature senescence.

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Section: Discussionmentioning

confidence: 99%

Regulation of Cr(VI)-Induced Premature Senescence in L02 Hepatocytes by ROS-Ca2+-NF-κB Signaling

Zhang

Yang

Huang

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Oxidative stress is described as one of the primary mechanisms underlying Cr (VI) toxicity 19 . ROS‐induced oxidative stress has also been implicated in NF‐κB pathway activation 20 . Therefore, NAC, a known inhibitor of ROS, was used to evaluate the effect of ROS and NF‐κB pathway in Cr (VI)‐induced inflammation in the liver.…”

Section: Resultsmentioning

confidence: 99%

“…Some study also demonstrated that Cr (VI) induced mitophagy via the interaction of HMGA2 and PARK2 in A549 cells and lung tissue. 20 Cr (VI) could also inhibit the formation of neutrophil extracellular traps and promote the apoptosis of neutrophils via AMPK signaling pathway. 32…”

Section: Discussionmentioning

confidence: 99%

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Role of NF‐κB signaling pathway in hexavalent chromium‐induced hepatotoxicity

Shen

Kom

Huang

et al. 2023

Environmental Toxicology

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Hexavalent chromium Cr (VI) is a primary human carcinogen with damaging toxic effects on multiple organs. Cr (VI) exposure can induce hepatotoxicity through oxidative stress, but its exact mechanism of action was still unclear. In our study, a model of acute Cr (VI) induced liver injury was established by exposing mice to different concentrations (0, 40, 80, and 160 mg/kg) of Cr (VI); RNA‐seq was used to characterize changes in liver tissue transcriptome of C57BL/6 mice after exposing to 160 mg/kg Bw of Cr (VI). Changes in liver tissue structures, proteins, and genes were observed by hematoxylin and eosin (H&E), western blot, immunohistochemistry and RT‐PCR. After Cr (VI) exposure, abnormal liver tissue structure, hepatocyte injury, and hepatic inflammatory response were observed in mice in a dose‐dependent manner. RNA‐seq transcriptome results indicated that oxidative stress, apoptosis, and inflammatory response pathways were increased after Cr (VI) exposure; KEGG pathway analysis found that activation of NF‐κB signaling pathway was significantly upregulated. Consistent with the RNA‐seq results, immunohistochemistry showed that Cr (VI) exposure resulted in infiltrating of Kupffer cells and neutrophils, increasing expression of inflammatory factors (TNF‐α, IL‐6, IL‐1β), and activating of NF‐κB signaling pathways (p‐IKKα/β and p‐p65). However, ROS inhibitor, N‐acetyl‐L‐cysteine (NAC), could reduce infiltration of Kupffer cells and neutrophils and expression of inflammatory factors. Besides, NAC could inhibit NF‐κB signaling pathway activation, and alleviate Cr (VI)‐induced liver tissue damage. Our findings strongly suggested that inhibition of ROS by NAC might help in the development of new strategies for Cr (VI)‐associated liver fibrosis. Our findings revealed for the first time that Cr (VI) induced liver tissue damage through the inflammatory response mediated by the NF‐κB signaling pathway, and inhibition of ROS by NAC might help in the development of new strategies for Cr (VI)‐associated hepatotoxicity.

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“…In contrast, fewer genes were identified that conferred a growth advantage (ie, synthetic rescue) when disrupted concomitantly with HMGA2 overexpression (supplemental Table 2). This included a known HMGA2-interacting partner, PARK2 (Parkin E3 ubiquitinprotein ligase) 34 ; however, no significant enrichment for canonical pathways was observed.…”

Section: Genome-wide Search For Vulnerabilities Associated With Hmga2...mentioning

confidence: 98%

HMGA2 expression defines a subset of human AML with immature transcriptional signature and vulnerability to G2/M inhibition

et al. 2022

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High Mobility Group AT-hook 2 (HMGA2) is a non-histone chromatin-binding protein which is normally expressed in stem cells of various tissues and aberrantly detected in several tumor types. We recently observed that one fourth of human Acute Myeloid Leukemia (AML) specimens express HMGA2, which associates with a very poor prognosis. We now present results indicating that HMGA2+ AMLs share a distinct transcriptional signature representing an immature phenotype. Using single cell analyses, we showed that HMGA2 is expressed in CD34+ subsets of stem cells and early progenitors, whether normal or derived from AML specimens. Of interest, we found that one of the strongest gene expression signatures associated with HMGA2 in AML is the upregulation of G2/M checkpoint genes. Whole genome CRISPR/Cas9 screening in HMGA2 overexpressing cells further revealed a synthetic lethal interaction with several G2/M checkpoint genes. Accordingly, small molecules that target G2/M proteins were preferentially active in vitro and in vivo on HMGA2+ AML specimens. Together, our findings suggest that HMGA2 is a key functional determinant in AML and is associated with stem cell features, G2/M status and related drug sensitivity.

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Cr (VI) induced mitophagy via the interaction of HMGA2 and PARK2

Cited by 7 publications

References 45 publications

Regulation of Cr(VI)-Induced Premature Senescence in L02 Hepatocytes by ROS-Ca2+-NF-κB Signaling

Regulation of Cr(VI)-Induced Premature Senescence in L02 Hepatocytes by ROS-Ca2+-NF-κB Signaling

Role of NF‐κB signaling pathway in hexavalent chromium‐induced hepatotoxicity

HMGA2 expression defines a subset of human AML with immature transcriptional signature and vulnerability to G2/M inhibition

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