The superoxide dismutase mimetic MnTBAP prevents Fas-induced acute liver failure in the mouse

Malassagne, Benoı̂t; Ferret, Pierre–Jacques; Hammoud, Renaud; Tulliez, M; Bedda, Sassia; Trebeden, Hélène; Jaffray, Patrick; Calmus, Yvon; Weill, Bernard; Batteux, Frédéric

doi:10.1053/gast.2001.29590

Cited by 79 publications

(58 citation statements)

References 27 publications

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“…The generation of mitochondrial ROS in the form of superoxide, the species produced by complex I dysfunction, 41 was previously shown to be necessary for killer lymphocyte-mediated death since superoxide scavengers virtually completely inhibit death. 17,42 Here we further show that GB-mediated mitocentric ROS are necessary for optimal apoptogenic factor release, pointing out that factor release need two independent steps, (1) the permeabilization of the mitochondrial outer membrane following GB cleavage of Bid, which trigger Bax/ Bak oligomerization and MOMP, (2) ROS that untether the apoptogenic factors within the intermembrane space for their release into the cytosol. Mitocentric ROS are also required for proper oligonucleosomal DNA fragmentation.…”

Section: Discussionmentioning

confidence: 52%

Granzyme B-induced mitochondrial ROS are required for apoptosis

et al. 2014

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Caspases and the cytotoxic lymphocyte protease granzyme B (GB) induce reactive oxygen species (ROS) formation, loss of transmembrane potential and mitochondrial outer membrane permeabilization (MOMP). Whether ROS are required for GBmediated apoptosis and how GB induces ROS is unclear. Here, we found that GB induces cell death in an ROS-dependent manner, independently of caspases and MOMP. GB triggers ROS increase in target cell by directly attacking the mitochondria to cleave NDUFV1, NDUFS1 and NDUFS2 subunits of the NADH: ubiquinone oxidoreductase complex I inside mitochondria. This leads to mitocentric ROS production, loss of complex I and III activity, disorganization of the respiratory chain, impaired mitochondrial respiration and loss of the mitochondrial cristae junctions. Furthermore, we have also found that GB-induced mitocentric ROS are necessary for optimal apoptogenic factor release, rapid DNA fragmentation and lysosomal rupture. Interestingly, scavenging the ROS delays and reduces many of the features of GB-induced death. Consequently, GB-induced ROS significantly promote apoptosis. Cell Death and Differentiation (2015) 22, 862-874; doi:10.1038/cdd.2014.180; published online 31 October 2014To induce cell death, human granzyme B (GB) activates effector caspase-3 or acts directly on key caspase substrates, such as the proapoptotic BH3 only Bcl-2 family member Bid, inhibitor of caspase-activated DNase (ICAD), poly-(ADPribose) polymerase-1 (PARP-1), lamin B, nuclear mitotic apparatus protein 1 (NUMA1), catalytic subunit of the DNAdependent protein kinase (DNA-PKcs) and tubulin. [1][2][3] Consequently, caspase inhibitors have little effect on human GB-mediated cell death and DNA fragmentation. 2 GB causes reactive oxygen species (ROS) production, dissipation of the mitochondrial transmembrane potential (ΔΨm) and MOMP, which leads to the release of apoptogenic factors such as cytochrome c (Cyt c), HtrA2/Omi, endonuclease G (Endo G), Smac/Diablo and apoptosis-inducing factor, from the mitochondrial intermembrane space to the cytosol. [4][5][6][7][8][9][10][11] Interestingly, cells deficient for Bid, Bax and Bak are still sensitive to human GB-induced cell death, 5,11-13 suggesting that human GB targets the mitochondria in another way that needs to be characterized. Altogether, much attention has been focused on the importance of MOMP in the execution of GB-mediated cell death, leaving unclear whether ROS production is a bystander effect or essential to the execution of GBinduced apoptosis. The mitochondrial NADH: ubiquinone oxidoreductase complex I is a key determinant in steadystate ROS production. This 1 MDa complex, composed of 44 subunits, 14 couples the transfer of two electrons from NADH to ubiquinone with the translocation of four protons to generate the ΔΨm. The importance of ROS has been previously demonstrated for caspase-3 and granzyme A (GA) pathways through the cleavage of NDUFS1 and NDUFS3, respectively. [15][16][17][18] GA induces cell death in a Bcl-2-insensitive and caspase-and MOMP-indepen...

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Section: Discussionmentioning

confidence: 52%

Granzyme B-induced mitochondrial ROS are required for apoptosis

et al. 2014

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“…FasL/Fas interaction induced the death of hepatocytes, predominantly by generation of reactive oxygen species and mitochondrial disruption. 3 The primary role of mitochondria during Fas-mediated apoptosis has been demonstrated in Bcl-2 and Bcl-xL transgenic mice. Bcl-xL or Bcl-2 overexpression blocked programmed cell death by inhibiting cytochrome c release from mitochondria and prevented Fas-mediated apoptosis of hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative damage plays a prominent role in hepatic apoptosis mediated via caspase activation. 3 Partial hepatectomy was reported to prevent hepatocyte apoptosis in response to Fas engagement, and alternatively Fas engagement accelerated liver regeneration after hepatectomy. These results suggested that factors triggered by the growth response protected mice against the lethal effects of Fas.…”

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confidence: 99%

Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice

et al. 2006

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Reg2/RegIII␤ is the murine homologue of the human secreted HIP/PAP C-type lectin. HIP/PAP transgenic mice were protected against acetaminophen-induced acute liver failure and were stimulated to regenerate post-hepatectomy. To assess the role of Reg2, we used Reg2؊/؊ mice in a model of fulminant hepatitis induced by Fas and in the post-hepatectomy regeneration. Within 4 hours of J0-2 treatment (0.5 g/g), only 50% of the Reg2؊/؊ mice were alive but with an increased sensitivity to Fas-induced oxidative stress and a decreased level of Bcl-xL. In contrast, HIP/PAP transgenic mice were resistant to Fas, with HIP/PAP serving as a sulfhydryl buffer to slow down decreases in glutathione and Bcl-xL. In Reg2؊/؊ mice, liver regeneration was markedly impaired, with 29% mortality and delay of the S-phase and the activation of ERK1/2 and AKT. Activation of STAT3 began on time at 3 hours but persisted strongly up to 72 hours despite significant accumulation of SOCS3. Thus, Reg2 deficiency induced exaggerated IL-6/STAT-3 activation and mito-inhibition. Because the Reg2 gene was activated between 6 and 24 hours after hepatectomy in wild-type mice, Reg2 could mediate the TNF-␣/IL-6 priming signaling by exerting a negative feedback on STAT3/IL-6 activation to allow the hepatocytes to progress through the cell cycle. In conclusion, Reg2 deficiency enhanced liver sensitivity to Fas-induced oxidative stress and delayed liver regeneration with persistent TNF-␣/IL6/STAT3 signaling. In contrast, overexpression of human HIP/PAP promoted liver resistance to Fas and accelerated liver regeneration with early activation/deactivation of STAT3. Reg2/HIP/PAP is therefore a critical mitogenic and antiapoptotic factor for the liver. (HEPATOLOGY 2006;44:1452-1464 F as/FasL (APO-1, CD95) interaction is involved in many pathological situations such as graft-versushost disease, liver transplant and major surgical resection, hepatitis B and C, acute alcoholic hepatitis, drug overdose, and some biliary diseases. Fas activation-induced acute liver failure is characterized by massive hepatic necrosis/apoptosis. Survival of patients depends on the speed with which quiescent liver cells re-enter the cell

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“…3,4 On the other hand, hepatocyte apoptosis and liver injury could be also caused by Fas activation induced by Fas ligand-bearing T cells or agonistic antibodies. 2,3 Although multiple death mechanisms can be activated by the death receptors, generation of reactive oxygen species (ROS) is a critical one, [5][6][7][8][9][10][11][12][13] and antioxidants have been shown to alleviate cell death induced by TNF-␣ 9,14 or Fas 7,15 activation. Despite the importance of ROS, the mechanisms of their generation remain controversial and unresolved.…”

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confidence: 99%

Bid-dependent generation of oxygen radicals promotes death receptor activation-induced apoptosis in murine hepatocytes

et al. 2004

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Activation of tumor necrosis factor receptor 1 or Fas leads to the generation of reactive oxygen species, which are important to the cytotoxic effects of tumor necrosis factor ␣ (TNF-␣) or Fas ligand. However, how these radicals are generated following receptor ligation is not clear. Using primary hepatocytes, we found that TNF-␣ or anti-Fas antibodyinduced burst of oxygen radicals was mainly derived from the mitochondria. We discovered that Bid-a pro-death Bcl-2 family protein activated by ligated death receptors-was the main intracellular molecule signaling the generation of the radicals by targeting to the mitochondria and that the majority of oxygen radical production was dependent on Bid. Reactive oxygen species contributed to cell death and caspase activation by promoting FLICE-inhibitory protein degradation and mitochondrial release of cytochrome c. For the latter part, the oxygen radicals did not affect Bak oligomerization but instead promoted mitochondrial cristae reorganization and membrane lipid peroxidation. Antioxidants could reverse these changes and therefore protect against TNF-␣ or anti-Fas-induced apoptosis. In conclusion, our studies established the signaling pathway from death receptor engagement to oxygen radical generation and determined the mechanism by which reactive oxygen species contributed to hepatocyte apoptosis following death receptor activation. (HEPATOLOGY 2004;40:403-413.)

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The superoxide dismutase mimetic MnTBAP prevents Fas-induced acute liver failure in the mouse

Cited by 79 publications

References 27 publications

Granzyme B-induced mitochondrial ROS are required for apoptosis

Granzyme B-induced mitochondrial ROS are required for apoptosis

Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice

Bid-dependent generation of oxygen radicals promotes death receptor activation-induced apoptosis in murine hepatocytes

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