Dibutyl phthalate causes heart damage by disrupting Ca2+ transfer from endoplasmic reticulum to mitochondria and triggering subsequent pyroptosis

Li, Bo; Huo, Siming; Du, Jiayu; Zhang, Xuliang; Zhang, Jian; Wang, Qi; Song, Miao; Li, Yanfei

doi:10.1016/j.scitotenv.2023.164620

Cited by 13 publications

(6 citation statements)

References 50 publications

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“…43 In a mouse model of dibutyl phthalate–induced heart damage, ER stress suppression reduced mitochondrial calcium accumulation through the MAM, resulting in mtROS and NLRP3 inhibition and subsequent cardiomyocyte pyroptosis. 44 Silencing the MAM-associated protein FUNDC1 decreased ER-mitochondrial calcium exchange and suppressed mitochondrial calcium overload, leading to reduced cardiomyocyte necrosis caused by Sorafenib-induced myocardial toxicity. 45 The ER is an important intracellular calcium pool that regulates mitochondrial function by releasing calcium ions into the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury

Li,

Guan,

Gao

et al. 2024

Hepatology Communications

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Background: Fatty livers are widely accepted as marginal donors for liver transplantation but are more susceptible to liver ischemia and reperfusion (IR) injury. Increased macrophage-related inflammation plays an important role in the aggravation of fatty liver IR injury. Here, we investigate the precise mechanism by which endoplasmic reticulum (ER) stress activates macrophage NOD-like receptor thermal protein domain–associated protein 3 (NLRP3) signaling by regulating mitochondrial calcium overload in fatty liver IR. Methods: Control- and high-fat diet-fed mice were subjected to a partial liver IR model. The ER stress, mitochondrial calcium levels, and NLRP3 signaling pathway in macrophages were analyzed. Results: Liver steatosis exacerbated liver inflammation and IR injury and enhanced NLRP3 activation in macrophages. Myeloid NLRP3 deficiency attenuated intrahepatic inflammation and fatty liver injury following IR. Mechanistically, increased ER stress and mitochondrial calcium overload were observed in macrophages obtained from mouse fatty livers after IR. Suppression of ER stress by tauroursodeoxycholic acid effectively downregulated mitochondrial calcium accumulation and suppressed NLRP3 activation in macrophages, leading to decreased inflammatory IR injury in fatty livers. Moreover, Xestospongin-C–mediated inhibition of mitochondrial calcium influx decreased reactive oxygen species (ROS) expression in macrophages after IR. Scavenging of mitochondrial ROS by mito-TEMPO suppressed macrophage NLRP3 activation and IR injury in fatty livers, indicating that excessive mitochondrial ROS production was responsible for macrophage NLRP3 activation induced by mitochondrial calcium overload. Patients with fatty liver also exhibited upregulated activation of NLRP3 and the ER stress signaling pathway after IR. Conclusions: Our findings suggest that ER stress promotes mitochondrial calcium overload to activate ROS/NLRP3 signaling pathways within macrophages during IR-stimulated inflammatory responses associated with fatty livers.

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Section: Discussionmentioning

confidence: 99%

ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury

Li,

Guan,

Gao

et al. 2024

Hepatology Communications

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“…Previous studies have shown that LPS can induce ER stress and Ca 2+ release while inhibiting ER stress-mediated NLRP3 inflammasome activation, alleviating acute lung injury [ 34 ]. Additionally, ER stress has been found to trigger the release of mitochondrial ROS and the production of NLRP3, thereby inhibiting NLRP3 inflammasome-mediated pyroptosis and improving atherosclerotic heart disease [ 15 ]. Consistent with previous findings, our study demonstrated that the ER stress inhibitor 4-PBA could effectively inhibit LPS-induced cardiomyocyte pyroptosis by targeting the NLRP3/Caspase-1/GSDMD pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Although the role of IP3R2 in SIC and its underlying mechanism remain unknown, previous research has demonstrated that inhibiting ER stress can alleviate septic cardiomyopathy [ 13 , 14 ]. Additionally, ER stress has been shown to activate the NLRP3 inflammasome, leading to pyroptotic cell death in atherosclerosis [ 15 ], and the inhibition of ER stress has also been found to improve cardiac function in isoproterenol-induced heart failure rats by suppressing cardiomyocyte pyroptosis [ 16 ]. However, there is no evidence regarding the impact of ER stress on IP3R2 regarding septic cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

IP3R2-mediated Ca2+ release promotes LPS-induced cardiomyocyte pyroptosis via the activation of NLRP3/Caspase-1/GSDMD pathway

Wu,

Yang,

Zhang

et al. 2024

Cell Death Discov.

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Pyroptosis plays a crucial role in sepsis, and the abnormal handling of myocyte calcium (Ca2+) has been associated with cardiomyocyte pyroptosis. Specifically, the inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is a Ca2+ release channel in the endoplasmic reticulum (ER). However, the specific role of IP3R2 in sepsis-induced cardiomyopathy (SIC) has not yet been determined. Thus, this study aimed to investigate the underlying mechanism by which IP3R2 channel-mediated Ca2+ signaling contributes to lipopolysaccharide (LPS)—induced cardiac pyroptosis. The SIC model was established in rats by intraperitoneal injection of LPS (10 mg/kg). Cardiac dysfunction was assessed using echocardiography, and the protein expression of relevant signaling pathways was analyzed using ELISA, RT-qPCR, and western blot. Small interfering RNAs (siRNA) and an inhibitor were used to explore the role of IP3R2 in neonatal rat cardiomyocytes (NRCMs) stimulated by LPS in vitro. LPS-induced NLRP3 overexpression and GSDMD-mediated pyroptosis in the rats’ heart. Treatment with the NLRP3 inhibitor MCC950 alleviated LPS-induced cardiomyocyte pyroptosis. Furthermore, LPS increased ATP-induced intracellular Ca2+ release and IP3R2 expression in NRCMs. Inhibiting IP3R activity with xestospongin C (XeC) or knocking down IP3R2 reversed LPS-induced intracellular Ca2+ release. Additionally, inhibiting IP3R2 reversed LPS-induced pyroptosis by suppressing the NLRP3/Caspase-1/GSDMD pathway. We also found that ER stress and IP3R2-mediated Ca2+ release mutually regulated each other, contributing to cardiomyocyte pyroptosis. IP3R2 promotes NLRP3-mediated pyroptosis by regulating ER Ca2+ release, and the mutual regulation of IP3R2 and ER stress further promotes LPS-induced pyroptosis in cardiomyocytes.

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“…Studies have shown that LonP1 deficiency can damage the integrity of MAMs and mitochondrial fusion, which may lead to the activation of the unfolded protein response within the ER. This could potentially result in remodeling of the heart and eventual progression to HF ( Li et al, 2023 ).…”

Section: Mitochondria-associated Endoplasmic Reticulum Membranes Cont...mentioning

confidence: 99%

Mitochondria-associated endoplasmic reticulum membranes as a therapeutic target for cardiovascular diseases

Ding,

Liu,

Zhang

et al. 2024

Front. Pharmacol.

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Cardiovascular diseases (CVDs) are currently the leading cause of death worldwide. In 2022, the CVDs contributed to 19.8 million deaths globally, accounting for one-third of all global deaths. With an aging population and changing lifestyles, CVDs pose a major threat to human health. Mitochondria-associated endoplasmic reticulum membranes (MAMs) are communication platforms between cellular organelles and regulate cellular physiological functions, including apoptosis, autophagy, and programmed necrosis. Further research has shown that MAMs play a critical role in the pathogenesis of CVDs, including myocardial ischemia and reperfusion injury, heart failure, pulmonary hypertension, and coronary atherosclerosis. This suggests that MAMs could be an important therapeutic target for managing CVDs. The goal of this study is to summarize the protein complex of MAMs, discuss its role in the pathological mechanisms of CVDs in terms of its functions such as Ca2+ transport, apoptotic signaling, and lipid metabolism, and suggest the possibility of MAMs as a potential therapeutic approach.

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Dibutyl phthalate causes heart damage by disrupting Ca2+ transfer from endoplasmic reticulum to mitochondria and triggering subsequent pyroptosis

Cited by 13 publications

References 50 publications

ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury

ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury

IP3R2-mediated Ca2+ release promotes LPS-induced cardiomyocyte pyroptosis via the activation of NLRP3/Caspase-1/GSDMD pathway

Mitochondria-associated endoplasmic reticulum membranes as a therapeutic target for cardiovascular diseases

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