Inhibition of mitochondrial permeability transition and release of cytochrome c by anti-apoptotic nucleoside analogues

Xue, Luzheng; Borutaite, Vilma; Tolkovsky, Aviva M.

doi:10.1016/s0006-2952(02)01181-4

Cited by 41 publications

(28 citation statements)

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“…Under the influence of many kinds of stress factors such as ROS, Ca 2+ overloading, and toxin, mitochondrial ultrastructure and its function were easily damaged, then the active substance originally in mitochondria related to apoptosis including cytochrome C, was released into cytoplasm [14][15][16][17][18] . Recent progress in studies on apoptosis has revealed that cytochrome C is a pro-apoptotic factor.…”

Section: Discussionmentioning

confidence: 99%

Role of mitochondria in cell apoptosis during hepatic ischemia-reperfusion injury and protective effect of ischemic postconditioning

Sun¹

2004

WJG

102

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AIM:To investigate the role of mitochondria in cell apoptosis during hepatic ischemia-reperfusion injury and protective effect of ischemic postconditioning (IPC). METHODS:A rat model of acute hepatic ischemia-reperfusion was established, 24 healthy male Wistar rats were randomly divided into sham-operated group, ischemia-reperfusion group (IR) and IPC group. IPC was achieved by several brief pre-reperfusions followed by a persistent reperfusion. Concentration of malondialdehyde (MDA) and activity of several antioxidant enzymes in hepatic tissue were measured respectively. Apoptotic cells were detected by TdT-mediated dUTP-biotin nick end labeling (TUNEL) and expression of Bcl-2 protein was measured by immunohistochemical techniques. Moreover, mitochondrial ultrastructure and parameters of morphology of the above groups were observed by electron microscope. RESULTS:Compared with IR group, the concentration of MDA and the hepatocellular apoptotic index in IPC group was significantly reduced (P<0.05), while the activity of antioxidant enzymes and OD value of Bcl-2 protein were markedly enhanced (P<0.05). Moreover, the injury of mitochondrial ultrastructure in IPC group was also obviously relieved.

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Section: Discussionmentioning

confidence: 99%

Role of mitochondria in cell apoptosis during hepatic ischemia-reperfusion injury and protective effect of ischemic postconditioning

Sun¹

2004

WJG

102

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“…However, in several of these studies, autophagy occurred in cells thought to die by apoptosis, and it was presumed that autophagy triggered apoptosis, rather than playing a direct role in the death process. Moreover, 3-MA can inhibit kinases other than class III PI3K (18), some of which may independently affect death signaling, as well as inhibit the permeability transition in mitochondria (22). Thus, it is not possible to directly implicate autophagy in death execution from these 3-MA inhibitor studies.…”

Section: Figurementioning

confidence: 99%

Autophagy in cell death: an innocent convict?

Levine

Yuan

2005

Journal of Clinical Investigation

1,565

1,255

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The visualization of autophagosomes in dying cells has led to the belief that autophagy is a nonapoptotic form of programmed cell death. This concept has now been evaluated using cells and organisms deficient in autophagy genes. Most evidence indicates that, at least in cells with intact apoptotic machinery, autophagy is primarily a pro-survival rather than a pro-death mechanism. This review summarizes the evidence linking autophagy to cell survival and cell death, the complex interplay between autophagy and apoptosis pathways, and the role of autophagy-dependent survival and death pathways in clinical diseases.Cell biologists have long recognized the possibility that eukaryotic cells may undergo nonapoptotic forms of programmed cell death. Autophagy, a lysosomal pathway involving the bulk degradation of cytoplasmic contents, has been identified as a prime suspect in such death, and recent studies have implicated the autophagy pathway as a cause of nonapoptotic cellular demise. However, most evidence linking autophagy to cell death is circumstantial. Now, with new tools to assess causality, it is an opportune time to revisit the case of autophagy in cell death. Is autophagy an innocent bystander, a direct death execution pathway, a defense mechanism that ultimately fails in its mission to preserve cell viability, and/or a garbage disposal mechanism that cleans up remnants of a cell already committed to die? Autophagy is a regulated lysosomal degradation pathwayThe term autophagy (Greek, "to eat oneself") does not refer to a death process; it denotes the process of self-cannibalization through a lysosomal degradation pathway. Autophagy is the cell's major regulated mechanism for degrading long-lived proteins and the only known pathway for degrading organelles (reviewed in refs. 1, 2). During autophagy, an isolation membrane forms, presumably arising from a vesicular compartment known as the preautophagosomal structure, invaginates, and sequesters cytoplasmic constituents including mitochondria, endoplasmic reticulum, and ribosomes (Figure 1). The edges of the membrane fuse to form a double or multimembranous structure, known as the autophagosome or autophagic vacuole. The outer membrane of the autophagosome fuses with the lysosome (in mammalian cells) or vacuole (in yeast and plants) to deliver the inner membranous vesicle to the lumen of the degradative compartment. Degradation of the sequestered material generates nucleotides, amino acids, and free fatty acids that are recycled for macromolecular synthesis and ATP generation.Autophagy occurs at low basal levels in all cells to perform homeostatic functions (e.g., cytoplasmic and organelle turnover) but is rapidly upregulated when cells need to generate intracellular nutrients and energy (e.g., during starvation or trophic factor withdrawal), undergo architectural remodeling (e.g., during developmental transitions), or rid themselves of damaging cytoplasmic components (e.g., during oxidative stress, infection, and accumulation of protein aggregates). Nutritional...

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“…MOMP was induced by treatment with atractyloside (Atr), which binds to the adenine nucleotide transporter and increases the probability of MOMP. 19 Atr was active as it triggered Ca 2 þ -dependent mitochondrial swelling in the same solution we used to examine Tim23 degradation 20 (data not shown). Cohort samples were incubated in the presence of cyclosporine A (CsA) and ATP, inhibitors of Atr function.…”

Section: Resultsmentioning

confidence: 86%

“…Rat liver mitochondria were isolated in a sucrose buffer, washed and then incubated in K/MOPS buffer containing 5 mM nitrilotetraacetic acid and respiratory substrates. 20 Immunoblotting and immunofluorescence. Post-nuclear protein extracts were separated by SDS-PAGE, blotted, and analysed using enhanced chemiluminescence (Amersham).…”

Section: Methodsmentioning

confidence: 99%

Intra-mitochondrial degradation of Tim23 curtails the survival of cells rescued from apoptosis by caspase inhibitors

et al. 2008

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Caspase inhibition can extend the survival of cells undergoing apoptosis beyond the point of mitochondrial outer membrane permeabilisation (MOMP), but this does not confer long-term protection because caspase-independent death pathways emerge. Here, we describe a novel mechanism of mitochondrial self-destruction in caspase-inhibited cells, whose hallmark is the degradation of Tim23, the essential pore-forming component of the TIM23 inner membrane translocase. We show that Tim23 degradation occurs in cycling and post-mitotic cells, it is caspase-independent but Bax/Bak dependent, and it follows cytochrome c release. The proteolytic degradation of Tim23 is induced by MOMP and is mitochondrion-autonomous, as it also occurs in isolated mitochondria undergoing permeability transition. Degradation of Tim23 is selective, as expression of several other inner membrane proteins that regulate respiratory chain function is unaffected, and is not autophagic, as it occurs similarly in autophagy-proficient and -deficient (Atg-5 knockout) cells. Depleting Tim23 with siRNA is sufficient to inhibit cell proliferation and prevent long-term survival, while expression of degradation-resistant Tim23-GFP in mitochondria delays caspaseindependent cell death. Thus, mitochondrial autodigestion of Tim23 joins the array of processes contributing to caspaseindependent cell death. Because mitochondrial biogenesis requires a functional protein-import machinery, preventing Tim23 degradation might, therefore, be essential for repairing damaged mitochondria in chronic degenerative diseases. Apart from providing cellular ATP, mitochondria are also integral components of proapoptotic signalling. During apoptosis, mitochondrial outer membrane permeabilisation (MOMP) causes release of apoptogenic factors such as cytochrome c from the intermembrane space (IMS) to the cytoplasm. Cytochrome c-mediated activation of caspases via Apaf-1 is a dominant regulator of apoptosis.2 Although pan-specific caspase inhibitors can extend survival considerably depending on the cell type and death stimulus, caspaseindependent mechanisms of death execution take over in the long term. This has been ascribed to the action of other mitochondrial apoptogenic factors, such as AIF or EndoG.2 In addition, autophagy, which is co-activated by many apoptotic stimuli, has pro-death activity when apoptosis execution is impaired. 3,4 Exploiting mechanisms that suppress mitochondrial dysfunction and its deleterious follow-on effects is an obvious starting point for the development of treatments against loss of irreplaceable cells during neurodegenerative diseases, stroke, or myocardial infarction. However, therapeutic strategies should also address ways to mend defective mitochondria, thereby hopefully achieving long-term protection. Therefore, it is important to assess whether damaged mitochondria retain a functional import machinery so that the supply of cytoplasmic proteins is maintained.Here we focus on Tim23, the eponymous constituent of the TIM23 complex that forms the crucia...

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Inhibition of mitochondrial permeability transition and release of cytochrome c by anti-apoptotic nucleoside analogues

Cited by 41 publications

References 42 publications

Role of mitochondria in cell apoptosis during hepatic ischemia-reperfusion injury and protective effect of ischemic postconditioning

Role of mitochondria in cell apoptosis during hepatic ischemia-reperfusion injury and protective effect of ischemic postconditioning

Autophagy in cell death: an innocent convict?

Intra-mitochondrial degradation of Tim23 curtails the survival of cells rescued from apoptosis by caspase inhibitors

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