Translocation of Heme Oxygenase-1 to Mitochondria Is a Novel Cytoprotective Mechanism against Non-steroidal Anti-inflammatory Drug-induced Mitochondrial Oxidative Stress, Apoptosis, and Gastric Mucosal Injury

Bindu, Samik; Pal, Chiranjib; Dey, Sumanta; Goyal, Manish; Alam, Athar; Iqbal, Mohammad; Dutta, Shubham; Sarkar, Souvik; Kumar, Rahul; Maity, Pallab; Bandyopadhyay, Uday

doi:10.1074/jbc.m111.279893

Cited by 94 publications

(50 citation statements)

References 98 publications

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“…However, the loss of the C-terminal ER-insertion site [15] suggests detachment of ER-bound full-length HO-1 prior to translocation to mitochondria. Our findings are in line with previous reports that mtHO-1 contributes to mitochondrial heme turnover [21], preserves ATP-levels [22] and is intrinsically involved in cytoprotection [23] by reducing tissue injury and oxidative stress. While mtHO-1 did not reduce oxidative damage in our model, we found improved respiration control and body-weight increase after its appearance between 2 and 5 weeks.…”

Section: Discussionsupporting

confidence: 93%

“…Interestingly, HO-1 was previously found not only in endoplasmic reticulum but can localize to mitochondria (mtHO-1) where it contributes to cytoprotection, regulates mitochondrial heme content and mitochondrial metabolic function [21], protects from loss of ATP [22] and reduces oxidative stress [23]. As expected, HO-1 levels in total homogenate paralleled the nuclear fraction of Nrf2 (Fig.…”

Section: Resultssupporting

confidence: 71%

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Transition between Acute and Chronic Hepatotoxicity in Mice Is Associated with Impaired Energy Metabolism and Induction of Mitochondrial Heme Oxygenase-1

et al. 2013

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The formation of protein inclusions is frequently associated with chronic metabolic diseases. In mice, short-term intoxication with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) leads to hepatocellular damage indicated by elevated serum liver enzyme activities, whereas only minor morphological changes are observed. Conversely, chronic administration of DDC for several weeks results in severe morphological damage, characterized by hepatocellular ballooning, disruption of the intermediate filament cytoskeleton, and formation of Mallory-Denk bodies consisting predominantly of misfolded keratins, Sqstm1/p62, and heat shock proteins. To evaluate the mechanistic underpinnings for this dichotomy we dissected the time-course of DDC intoxication for up to 10 weeks. We determined body weight change, serum liver enzyme activities, morphologic alterations, induction of antioxidant response (heme oxygenase-1, HO-1), oxidative damage and ATP content in livers as well as respiration, oxidative damage and the presence and activity of HO-1 in endoplasmic reticulum and mitochondria (mtHO-1). Elevated serum liver enzyme activity and oxidative liver damage were already present at early intoxication stages without further subsequent increase. After 2 weeks of intoxication, mice had transiently lost 9% of their body weight, liver ATP-content was reduced to 58% of controls, succinate-driven respiration was uncoupled from ATP-production and antioxidant response was associated with the appearance of catalytically active mtHO-1. Oxidative damage was associated with both acute and chronic DDC toxicity whereas the onset of chronic intoxication was specifically associated with mitochondrial dysfunction which was maximal after 2 weeks of intoxication. At this transition stage, adaptive responses involving mtHO-1 were induced, indirectly leading to improved respiration and preventing further drop of ATP levels. Our observations clearly demonstrate principally different mechanisms for acute and chronic toxic damage.

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Section: Discussionsupporting

confidence: 93%

Section: Resultssupporting

confidence: 71%

Transition between Acute and Chronic Hepatotoxicity in Mice Is Associated with Impaired Energy Metabolism and Induction of Mitochondrial Heme Oxygenase-1

et al. 2013

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“…HO-1 catalyzes the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitutes a major intracellular source of CO (49). Previous studies show that induction and translocation of HO-1 to mitochondria prevents mitochondrial oxidative stress and tissue injury (3,4,10), suggesting that mitochondria are key targets of CO for regulation of the inflammasome. It is important to note that our exogenous treatment of CO may exert additional effects on mitochondria because of higher intracellular concentration of CO compared with endogenous CO derived from heme catabolism (49).…”

Section: Discussionmentioning

confidence: 97%

Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages

Jung

Moon

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Inflammasomes are cytosolic protein complexes that promote the cleavage of caspase-1, which leads to the maturation and secretion of proinflammatory cytokines, including interleukin-1β (IL-1β) and IL-18. Among the known inflammasomes, the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3)-dependent inflammasome is critically involved in the pathogenesis of various acute or chronic inflammatory diseases. Carbon monoxide (CO), a gaseous molecule physiologically produced in cells and tissues during heme catabolism, can act as an anti-inflammatory molecule and a potent negative regulator of Toll-like receptor signaling pathways. To date, the role of CO in inflammasome-mediated immune responses has not been fully investigated. Here, we demonstrated that CO inhibited caspase-1 activation and the secretion of IL-1β and IL-18 in response to lipopolysaccharide (LPS) and ATP treatment in bone marrow-derived macrophages. CO also inhibited IL-18 secretion in response to LPS and nigericin treatment, another NLRP3 inflammasome activation model. In contrast, CO did not suppress IL-18 secretion in response to LPS and poly(dA:dT), an absent in melanoma 2 (AIM2)-mediated inflammasome model. LPS and ATP stimulation induced the formation of complexes between NLRP3 and apoptosis-associated speck-like protein, or NLRP3 and caspase-1. CO treatment inhibited these molecular interactions that were induced by LPS and ATP. Furthermore, CO inhibited mitochondrial ROS generation and the decrease of mitochondrial membrane potential induced by LPS and ATP in macrophages. We also observed that the inhibitory effect of CO on the translocation of mitochondrial DNA into the cytosol was associated with suppression of cytokine secretion. Our results suggest that CO negatively regulates NLRP3 inflammasome activation by preventing mitochondrial dysfunction.

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“…To understand the effect of HO-1 on inflammation and/or restoration of liver function in this model, the use of an HO-1 inducer as well as an inhibitor was essential. ZnPP and CoPP are a well-known inhibitor and stimulator of HO-1, respectively (59,(96)(97)(98)(99)(100)(101)(102). However, both the protoporphyrins may have various effects on the expression of transforming growth factor beta (TGF-␤) (103), a cytokine that is intricately associated with the regulation of inflammation (104).…”

Section: Discussionmentioning

confidence: 99%

“…Chloroform was used to extract the bilirubin formed in the mixture, and its concentration was estimated from its extinction coefficient (40 mM/liter/cm) by measuring the A 464 -530 . The activity of HO-1 was expressed as nmol of bilirubin/mg protein/h (58,59).…”

Section: Methodsmentioning

confidence: 99%

Association of Heme Oxygenase 1 with the Restoration of Liver Function after Damage in Murine Malaria by Plasmodium yoelii

et al. 2014

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The liver efficiently restores function after damage induced during malarial infection once the parasites are cleared from the blood. However, the molecular events leading to the restoration of liver function after malaria are still obscure. To study this, we developed a suitable model wherein mice infected with Plasmodium yoelii (45% parasitemia) were treated with the antimalarial ␣/␤-arteether to clear parasites from the blood and, subsequently, restoration of liver function was monitored. Liver function tests clearly indicated that complete recovery of liver function occurred after 25 days of parasite clearance. Analyses of proinflammatory gene expression and neutrophil infiltration further indicated that hepatic inflammation, which was induced immediately after parasite clearance from the blood, was gradually reduced. Moreover, the inflammation in the liver after parasite clearance was found to be correlated positively with oxidative stress and hepatocyte apoptosis. We investigated the role of heme oxygenase 1 (HO-1) in the restoration of liver function after malaria because HO-1 normally renders protection against inflammation, oxidative stress, and apoptosis under various pathological conditions. The expression and activity of HO-1 were found to be increased significantly after parasite clearance. We even found that chemical silencing of HO-1 by use of zinc protoporphyrin enhanced inflammation, oxidative stress, hepatocyte apoptosis, and liver injury. In contrast, stimulation of HO-1 by cobalt protoporphyrin alleviated liver inflammation and reduced oxidative stress, hepatocyte apoptosis, and associated tissue injury. Therefore, we propose that selective induction of HO-1 in the liver would be beneficial for the restoration of liver function after parasite clearance.

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Translocation of Heme Oxygenase-1 to Mitochondria Is a Novel Cytoprotective Mechanism against Non-steroidal Anti-inflammatory Drug-induced Mitochondrial Oxidative Stress, Apoptosis, and Gastric Mucosal Injury

Cited by 94 publications

References 98 publications

Transition between Acute and Chronic Hepatotoxicity in Mice Is Associated with Impaired Energy Metabolism and Induction of Mitochondrial Heme Oxygenase-1

Transition between Acute and Chronic Hepatotoxicity in Mice Is Associated with Impaired Energy Metabolism and Induction of Mitochondrial Heme Oxygenase-1

Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages

Association of Heme Oxygenase 1 with the Restoration of Liver Function after Damage in Murine Malaria by Plasmodium yoelii

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