Implication of mitochondrial dysfunction and cell death in cold preservation – warm reperfusion-induced hepatocyte injury

2006 ◽  
Vol 84 (5) ◽  
pp. 547-554 ◽  
Author(s):  
Marjolaine Duval ◽  
Catherine Plin ◽  
Aziz Elimadi ◽  
Diane Vallerand ◽  
Jean-Paul Tillement ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Cytochrome C ◽  
Mitochondrial Dysfunction ◽  
Isolated Hepatocytes ◽  
Mitochondrial Pathway ◽  
Liver Graft ◽  
Isolated Cells ◽  
Hepatocyte Injury ◽  
Effector Caspase

Cold ischemia – warm reperfusion (CI/WR) injury of liver transplantation involves hepatocyte cell death, the nature and underlying mechanisms of which remain unclear. Isolated hepatocytes and isolated perfused livers were used to determine the prevalence of necrosis and apoptosis as well as mitochondrial dysfunction. In isolated cells, propidium iodide and Hoechst 33342 staining showed a cold-storage, time-dependent increase in necrosis, whereas apoptosis was minimal even after 48 h of hypothermia. Nonetheless, a progressive loss of mitochondrial membrane potential was observed. Translocation of mitochondrial cytochrome c toward microsomes occurred within 24 h of CI/WR, with cytochrome c reaching the cytosol later. Mitochondria isolated from whole livers subjected to CI/WR also display reduced metabolic parameters and increased susceptibility to swelling. These events are associated with increased activity of major initiator (caspase 9) and effector (caspase 3) caspases. The results demonstrate that CI/WR induces mitochondrial dysfunction in isolated cells and in the whole organ; only in the latter is that sufficient to trigger the classical mitochondrial pathway of apoptosis. Our study also provides evidence for the involvement of endoplasmic reticulum stress in CI/WR hepatocyte injury. Combined protection of mitochondria and endoplasmic reticulum may thus represent an innovative therapeutic avenue to enhance liver graft viability and functional integrity.

scholarly journals Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

APOPTOSIS ◽  
2021 ◽  
Author(s):  
Michela Raimondi ◽  
Fabrizio Fontana ◽  
Monica Marzagalli ◽  
Matteo Audano ◽  
Giangiacomo Beretta ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Atp Synthesis ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Ros Generation ◽  
Therapy Outcomes ◽  
Human Melanoma Cells ◽  
Oxphos Complex

Abstract Melanoma is an aggressive tumor with still poor therapy outcomes. δ-tocotrienol (δ-TT) is a vitamin E derivative displaying potent anti-cancer properties. Previously, we demonstrated that δ-TT triggers apoptosis in human melanoma cells. Here, we investigated whether it might also activate paraptosis, a non-canonical programmed cell death. In accordance with the main paraptotic features, δ-TT was shown to promote cytoplasmic vacuolization, associated with endoplasmic reticulum/mitochondrial dilation and protein synthesis, as well as MAPK activation in A375 and BLM cell lines. Moreover, treated cells exhibited a significant reduced expression of OXPHOS complex I and a marked decrease in oxygen consumption and mitochondrial membrane potential, culminating in decreased ATP synthesis and AMPK phosphorylation. This mitochondrial dysfunction resulted in ROS overproduction, found to be responsible for paraptosis induction. Additionally, δ-TT caused Ca2+ homeostasis disruption, with endoplasmic reticulum-derived ions accumulating in mitochondria and activating the paraptotic signaling. Interestingly, by using both IP3R and VDAC inhibitors, a close cause-effect relationship between mitochondrial Ca2+ overload and ROS generation was evidenced. Collectively, these results provide novel insights into δ-TT anti-melanoma activity, highlighting its ability to induce mitochondrial dysfunction-mediated paraptosis. Graphic Abstract δ-tocotrienol induces paraptotic cell death in human melanoma cells, causing endoplasmic reticulum dilation and mitochondrial swelling. These alterations induce an impairment of mitochondrial function, ROS production and calcium overload.

Mitochondrial dysfunction in CD47-mediated caspase-independent cell death: ROS production in the absence of cytochrome c and AIF release

Biochimie ◽  
2003 ◽  
Vol 85 (8) ◽  
pp. 741-746 ◽  
Author(s):  
Gaël Roué ◽  
Natacha Bitton ◽  
Victor J. Yuste ◽  
Thomas Montange ◽  
Manuel Rubio ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Mitochondrial Dysfunction ◽  
Ros Production

Overexpression of the Cell Death Suppressor Bcl-w in Ischemic Brain: Implications for a Neuroprotective Role via the Mitochondrial Pathway

2000 ◽  
Vol 20 (3) ◽  
pp. 620-630 ◽  
Author(s):  
Chaohua Yan ◽  
Jun Chen ◽  
Dexi Chen ◽  
Manabu Minami ◽  
Wei Pei ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Permeability Transition ◽  
Brain Mitochondria ◽  
Mitochondrial Pathway ◽  
Border Zone ◽  
Dependent Manner ◽  
High Concentration ◽  
Ischemic Brain ◽  
Cell Death Suppressor

Bcl-w is a newly described cell death suppressor member of the Bcl-2 gene family. As these genes may have a role in the outcome of ischemic brain injury, the regional expression of Bcl-w protein in rat brain was examined at 6 to 72 hours after 90 minutes of transient middle cerebral artery occlusion. Bcl-w protein, although constitutively expressed at low levels in nonischemic brain, was found to be overexpressed in ischemic brain at all time points studied. Up-regulation of Bcl-w protein was particularly abundant in the penumbral region of the cortex and mainly in cells lacking DNA fragmentation. In the cortical penumbra, Bcl-w protein was detected predominantly in neurons and showed mitochondrial localization, as determined using double-label immunohistochemistry. Bcl-w expression was also detectable, to a lesser extent, in reactive astrocytes in the infarct border zone and in microvessel walls in the infarct regions. At the mechanistic level, incubation of isolated brain mitochondria with the addition of recombinant Bax or high concentration of calcium resulted in release of cytochrome c from the mitochondria. In the presence of recombinant Bcl-w protein, however, the release of cytochrome c induced by Bax or calcium was largely inhibited. Further, recombinant Bcl-w protein inhibited calcium-induced loss of mitochondrial transmembrane potential, indicative of permeability transition, in a dose-dependent manner. These results suggest that Bcl-w may be an endogenous neuroprotectant against ischemic neuronal death and that, like its analogues such as Bcl-2 and Bcl-x-long, Bcl-w may achieve this protection via the mitochondrial death-regulatory pathway.

scholarly journals Hepatocyte Death: A Clear and Present Danger

2010 ◽  
Vol 90 (3) ◽  
pp. 1165-1194 ◽  
Author(s):  
Harmeet Malhi ◽  
Maria Eugenia Guicciardi ◽  
Gregory J. Gores
Keyword(s):  
Cell Death ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Enterohepatic Circulation ◽  
Tissue Injury ◽  
Death Receptor ◽  
Mitochondrial Pathway ◽  
Hepatocyte Injury ◽  
The Unfolded Protein Response

The hepatocyte is especially vulnerable to injury due to its central role in xenobiotic metabolism including drugs and alcohol, participation in lipid and fatty acid metabolism, its unique role in the enterohepatic circulation of bile acids, the widespread prevalence of hepatotropic viruses, and its existence within a milieu of innate immune responding cells. Apoptosis and necrosis are the most widely recognized forms of hepatocyte cell death. The hepatocyte displays many unique features regarding cell death by apoptosis. It is quite susceptible to death receptor-mediated injury, and its death receptor signaling pathways involve the mitochondrial pathway for efficient cell killing. Also, death receptors can trigger lysosomal disruption in hepatocytes which further promote cell and tissue injury. Interestingly, hepatocytes are protected from cell death by only two anti-apoptotic proteins, Bcl-xL and Mcl-1, which have nonredundant functions. Endoplasmic reticulum stress or the unfolded protein response contributes to hepatocyte cell death during alterations of lipid and fatty acid metabolism. Finally, the current information implicating RIP kinases in necrosis provides an approach to more fully address this mode of cell death in hepatocyte injury. All of these processes contributing to hepatocyte injury are discussed in the context of potential therapeutic strategies.

scholarly journals The role of ARK in stress-induced apoptosis in Drosophila cells

2002 ◽  
Vol 156 (6) ◽  
pp. 1077-1087 ◽  
Author(s):  
Katja C. Zimmermann ◽  
Jean-Ehrland Ricci ◽  
Nathalie M. Droin ◽  
Douglas R. Green
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Molecular Mechanisms ◽  
Mitochondrial Pathway ◽  
Exact Function ◽  
Increased Sensitivity ◽  
Induced Apoptosis ◽  
Drosophila Cells ◽  
Pronounced Inhibition

The molecular mechanisms of apoptosis are highly conserved throughout evolution. The homologs of genes essential for apoptosis in Caenorhabditis elegans and Drosophila melanogaster have been shown to be important for apoptosis in mammalian systems. Although a homologue for CED-4/apoptotic protease-activating factor (Apaf)-1 has been described in Drosophila, its exact function and the role of the mitochondrial pathway in its activation remain unclear. Here, we used the technique of RNA interference to dissect apoptotic signaling pathways in Drosophila cells. Inhibition of the Drosophila CED-4/Apaf-1–related killer (ARK) homologue resulted in pronounced inhibition of stress-induced apoptosis, whereas loss of ARK did not protect the cells from Reaper- or Grim-induced cell death. Reduction of DIAP1 induced rapid apoptosis in these cells, whereas the inhibition of DIAP2 expression did not but resulted in increased sensitivity to stress-induced apoptosis; apoptosis in both cases was prevented by inhibition of ARK expression. Cells in which cytochrome c expression was decreased underwent apoptosis induced by stress stimuli, Reaper or Grim. These results demonstrate the central role of ARK in stress-induced apoptosis, which appears to act independently of cytochrome c. Apoptosis induced by Reaper or Grim can proceed via a distinct pathway, independent of ARK.

scholarly journals Sophorolipid exhibits antifungal activity by ROS mediated endoplasmic reticulum stress and mitochondrial dysfunction pathways in Candida albicans

RSC Advances ◽  
2019 ◽  
Vol 9 (71) ◽  
pp. 41639-41648 ◽  
Author(s):  
Farazul Haque ◽  
Nitish Kumar Verma ◽  
Mohammad Alfatah ◽  
Swati Bijlani ◽  
Mani Shankar Bhattacharyya
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Ros Generation

Sophorolipid induces ROS generation in C. albicans leading to mitochondrial dysfunction and ER stress followed by the release of Ca2+ ions (from the ER lumen) that enter mitochondria and further magnify ROS generation leading to cell death.

scholarly journals Piper sarmentosum induced apoptosis via mitochondrial pathway in human lung adenocarcinoma cells, A549

2016 ◽  
Vol 15 (1) ◽  
Author(s):  
Azila Sirajudeen ◽  
Aisyah Hanani Mohd Tahir ◽  
Radiah Abdul Ghani
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Death ◽  
Cytochrome C ◽  
Treatment Strategies ◽  
A549 Cells ◽  
Annexin V ◽  
Mitochondrial Pathway ◽  
Cell Cycle Profile ◽  
Induced Apoptosis

Introduction: Lung cancer has been reported as one of the most common types of cancer worldwide. Current cancer treatments like chemotherapy do not result in a complete cure and are known to cause side effects in the patients. Therefore, alternative treatment strategies are being explored, one of which is to investigate the potential of the local herbs in this regard. Piper sarmentosum (daun kaduk) has received much attention due to its anti-cancer properties in A549 cells. In this study, the cell cycle profile and mechanisms of cell death induced by P. sarmentosum were investigated using a flow cytometer. Methods: The cell cycle profile changes were observed using propidium iodide staining while the type of cell death was analyzed using Annexin-V assay. Caspases -3/7,8 and 9 and cytochrome c assays were elucidated using flow cytometry analysis. Results: P.sarmentosum arrested the growth of A549 cells at G0/G1 phase. The Annexin V analysis revealed that P. sarmentosum exhibited significant induction of apoptosis after 24 h exposure. Caspases analysis showed that P. sarmentosum induced apoptosis through mitochondrial pathway, via the activation of caspase 3 and caspase 9. Meanwhile, cytochrome c analysis revealed that P. sarmentosum induced a mitochondrial pathway of cell death through the release of cytochrome c. Conclusions: Based on these preliminary findings, P. sarmentosum has a great potential as a dietary cancer treatment for lung cancer and may perhaps be used for lung cancer pharmacotherapy in the clinical settings in future.

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