Mitochondrial control of cell death

Kroemer, Guido; Reed, John C.

doi:10.1038/74994

Cited by 2,887 publications

(2,111 citation statements)

References 76 publications

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“…MMP represents a crucial check-point in the cascade of events leading to cell death, with far-reaching consequences for the pathophysiology of cell death, as well as for its pharmacological manipulation [7][8][9]. Thus, the meticulous investigation of the mechanisms of MMP is essential not only for a deeper comprehension of molecular biology phenomena, but also (and more importantly) to guide future therapeutical interventions.…”

Section: Discussionmentioning

confidence: 99%

“…Death-promoting stimuli originating from other subcellular compartments (e.g. the nucleus, lysosomes, the endoplasmic reticulum, or the cytosol) converge on mitochondria where they favor mitochondrial membrane permeabilization (MMP) [7][8][9]. Upon permeabilization of the mitochondrial outer membrane (OM), intermembrane space (IMS) proteins, that include caspase activators such as cytochrome c (Cyt c) [10], Omi/HtrA2 (Omi stress-regulated endoprotease/High temperature requirement protein A 2) [11,12] and Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP binding protein with a low pI) [13,14], as well as caspase-independent death effectors like apoptosis-inducing factor (AIF) [15,16] and endonuclease G (EndoG) [17], are released into the cytosol.…”

Section: Intrinsic and Extrinsic Apoptosis Pathwaysmentioning

confidence: 99%

“…Mitochondrial membrane permeabilization (MMP) represents a unifying feature of several models of cell death, and is commonly considered as the "point-of-no-return" in the sequence of events leading to apoptosis [7,31,32]. MMP occurs via multiple and complex mechanisms, which may involve only the OM or engage also the inner mitochondrial membrane (IM).…”

Section: Mitochondrial Membrane Permeabilizationmentioning

confidence: 99%

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Methods for the assessment of mitochondrial membrane permeabilization in apoptosis

et al. 2007

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Mitochondrial membrane permeabilization (MMP) is considered as the "point-of-no-return" in numerous models of programmed cell death. Indeed, mitochondria determine the intrinsic pathway of apoptosis, and play a major role in the extrinsic route as well. MMP affects the inner and outer mitochondrial membranes (IM and OM, respectively) to a variable degree. OM permeabilization culminates in the release of proteins that normally are confined in the mitochondrial intermembrane space (IMS), including caspase activators (e.g. cytochrome c) and caspase-independent death effectors (e.g. apoptosis-inducing factor). Partial IM permeabilization disrupts mitochondrial ion and volume homeostasis and dissipates the mitochondrial transmembrane potential ( m ). The assessment of early mitochondrial alterations allows for the identification of cells that are committed to die but have not displayed yet the apoptotic phenotype. Several

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Section: Discussionmentioning

confidence: 99%

Section: Intrinsic and Extrinsic Apoptosis Pathwaysmentioning

confidence: 99%

Section: Mitochondrial Membrane Permeabilizationmentioning

confidence: 99%

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Methods for the assessment of mitochondrial membrane permeabilization in apoptosis

et al. 2007

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“…16 Mitochondria respond to apoptotic signals with the release of caspase activating factors from the intermembrane space into the cytosol. 17 Caspases cleave cellular substrates and thereby modify their functions, which as a net effect, results in the complex phenotype of apoptosis. 18 One of the mechanisms of kinase activation in apoptotic cells depends on the cleavage by caspases which separate inhibitory domains from the catalytic domains.…”

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confidence: 99%

Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis

2003

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c-Abl protein tyrosine kinase plays an important role in cell cycle control and apoptosis. Furthermore, induction of apoptosis correlates with the activation of c-Abl. Here, we demonstrate the cleavage of c-Abl by caspases during apoptosis. Caspases separate c-Abl into functional domains including a Src-kinase, a fragment containing nuclear import sequences, a fragment with an actin-binding domain and nuclear export sequence. Caspase cleavage increases the kinase activity of c-Abl as demonstrated by in vitro kinase assays as well as by auto-and substrate phosphorylation. Cells in which c-Abl expression was knocked down by RNA interference resisted cisplatin-but not TNFa-induced apoptosis. A similar selective resistance against cisplatin-induced apoptosis was observed when cleavage resistant c-Abl was overexpressed in treated cells. Our data suggest the selective requirement of c-Abl cleavage by caspases for stressinduced, but not for TNFa-induced apoptosis.

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“…Recent progress has shown the central role of mitochondria in death signaling [38]. In certain situations, death stimuli induce an increase in the permeability of the outer mitochondrial membrane that releases apoptosis inducers, such as cytochrome c [39] and apoptosis-inducing factor (AIF) [40].…”

Section: Discussionmentioning

confidence: 99%

Dissociation of DNA damage and mitochondrial injury caused by hydrogen peroxide in SV-40 transformed lung epithelial cells

et al. 2002

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BackgroundSince lung epithelial cells are constantly being exposed to reactive oxygen intermediates (ROIs), the alveolar surface is a major site of oxidative stress, and each cell type may respond differently to oxidative stress. We compared the extent of oxidative DNA damage with that of mitochondrial injury in lung epithelial cells at the single cell level.ResultDNA damage and mitochondrial injury were measured after oxidative stress in the SV-40 transformed lung epithelial cell line challenged with hydrogen peroxide (H2O2). Single cell analysis of DNA damage was determined by assessing the number of 8-oxo-2-deoxyguanosine (8-oxo-dG) positive cells, a marker of DNA modification, and the length of a comet tail. Mitochondrial membrane potential, ΔΨm, was determined using JC-1. A 1 h pulse of H2O2 induced small amounts of apoptosis (3%). 8-oxo-dG-positive cells and the length of the comet tail increased within 1 h of exposure to H2O2. The number of cells with reduced ΔΨm increased after the addition of H2O2 in a concentration-dependent manner. In spite of a continual loss of ΔΨm, DNA fragmentation was reduced 2 h after exposure to H2O2.ConclusionThe data suggest that SV-40 transformed lung epithelial cells are resistant to oxidative stress, showing that DNA damage can be dissociated from mitochondrial injury.

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Mitochondrial control of cell death

Abstract: In many instances, permeabilization of mitochondrial membranes is a rate-limiting step of apoptotic or necrotic cell demise. This has important consequences for the pathophysiology of cell death, as well as for its pharmacological control.

Cited by 2,887 publications

References 76 publications

Methods for the assessment of mitochondrial membrane permeabilization in apoptosis

Methods for the assessment of mitochondrial membrane permeabilization in apoptosis

Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis

Dissociation of DNA damage and mitochondrial injury caused by hydrogen peroxide in SV-40 transformed lung epithelial cells

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