Pathophysiology of mitochondrial cell death control

Vieira, Helena L.A.; Kroemer, Guido

doi:10.1007/s000180050486

Cited by 42 publications

(30 citation statements)

References 41 publications

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“…This observation is in line with the idea (see below) that mitochondria are key players in apoptosis triggered by some, but not all, stimuli (Green and Reed, 1998;Bernardi, 1999;Vieira and Kroemer, 1999;Duchen, 2000). Indeed, according to some authors, the apoptotic process is preceded by collapse of the mitochondrial potential, opening of a multiprotein structure named permeability transition pore (PTP), swelling of the matrix and rupture of the outer membrane with ensuing changes in the permeability of the outer mitochondrial membrane, and release of apoptogenic factors from mitochondria (Petronilli et al, 1994;Skulachev, 1996;Bernardi et al, 1998;Petit et al, 1998); see below.…”

Section: The Ca 2 þ Balletsupporting

confidence: 90%

Calcium and apoptosis: facts and hypotheses

et al. 2003

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Although longstanding experimental evidence has associated alterations of calcium homeostasis to cell death, only in the past few years the role of calcium in the signaling of apoptosis has been extensively investigated. In this review, we will summarize the current knowledge, focusing on (i) the effect of the proteins of the Bcl-2 family on ER Ca 2 þ levels, (ii) the action of the proteolytic enzymes of apoptosis on the Ca 2 þ signaling machinery, (iii) the ensuing alterations on the signaling patterns of extracellular stimuli, and (iv) the intracellular targets of 'apoptotic' Ca 2 þ signals, with special emphasis on the mitochondria and cytosolic Ca 2 þ -dependent enzymes.

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Section: The Ca 2 þ Balletsupporting

confidence: 90%

Calcium and apoptosis: facts and hypotheses

et al. 2003

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“…This type of permeabilization causes a partial release of proapoptotic factors such as cytochrome c (12,13). The members of the Bcl-2 family also interact with the mitochondrial permeability transition pore (34). Reversible permeabilization of the mitochondrial membrane by opening of the permeability transition pore also causes the release of proapoptotic factors from mitochondria.…”

Section: Breakdown Of Brain Mitochondria By Ca 2ϩ Rise and Hypoxiamentioning

confidence: 99%

Brain Mitochondria Are Primed by Moderate Ca2+ Rise upon Hypoxia/Reoxygenation for Functional Breakdown and Morphological Disintegration

Schild

Huppelsberg

Kahlert

et al. 2003

Journal of Biological Chemistry

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In animal models, brain ischemia causes changes in respiratory capacity, mitochondrial morphology, and cytochrome c release from mitochondria as well as a rise in cytosolic Ca 2؉ concentration. However, the causal relationship of the cellular processes leading to mitochondrial deterioration in brain has not yet been clarified. Here, by applying various techniques, we used isolated rat brain mitochondria to investigate how hypoxia/reoxygenation and nonphysiological Ca 2؉ concentrations in the low micromolar range affect active (state 3) respiration, membrane permeability, swelling, and morphology of mitochondria. Either transient hypoxia or a micromolar rise in extramitochondrial Ca 2؉ concentration, given as a single insult alone, slightly decreased active respiration. However, the combination of both insults caused devastating effects. These implied almost complete loss of active respiration, release of both NADH and cytochrome c, and rupture of mitochondria, as shown by electron microscopy. Mitochondrial respiration deteriorated even in the presence of cyclosporin A, documenting that membrane permeabilization occurred independent of mitochondrial permeability transition pore. Ca 2؉ has to enter the mitochondrial matrix in order to mediate this mitochondrial injury, because blockade of the mitochondrial Ca 2؉ -transport system by ruthenium red in combination with CGP37157 completely prevented damage. Furthermore, protection of respiration from Ca 2؉ -mediated damage by the adenine nucleotide ADP, but not by AMP, during hypoxia/ reoxygenation is consistent with the delayed susceptibility of brain mitochondria to prolonged hypoxia, which is observed in vivo.

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“…It is known that mitochondria play a crucial role in several processes and physiopathological situations, including apoptosis. 28,29 First of all, we found that HCW-2 cells did not have MRPs activity higher than HL-60 cells. Furthermore, HCW-2 cells showed resistance also to physical agents like g-rays, thus MRPs must be excluded as a possible mechanism of resistance to apoptosis in such cells.…”

Section: Discussionmentioning

confidence: 65%

Apoptosis-resistant phenotype in HL-60-derived cells HCW-2 is related to changes in expression of stress-induced proteins that impact on redox status and mitochondrial metabolism

et al. 2003

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The onset of resistance to drug-induced apoptosis of tumour cells is a major problem in cancer therapy. We studied a drugselected clone of promyelocytic HL-60 cells, called HCW-2, which display a complex resistance to a wide variety of apoptosis-inducing agents and we found that these cells show a dramatic increase in the expression of heat shock proteins (Hsps) 70 and 27, while the parental cell line does not. It is known that stress proteins such as Hsps can confer resistance to a variety of damaging agents other than heat shock, such as TNF-a, monocyte-induced cytoxicity, and also play a role in resistance to chemotherapy. This elevated expression of Hsps is paralleled by an increased activity of mitochondrial metabolism and pentose phosphate pathway, this latter leading to high levels of glucose-6-phosphate dehydrogenase and, consequently, of glutathione. Thus, the apoptotic-deficient phenotype is likely because of the presence of high levels of stress response proteins and GSH, which may confer resistance to apoptotic agents, including chemotherapic drugs. Moreover, the fact that in HCW-2 cells Hsp70 are mainly localised in mitochondria may account for the increased performances of mitochondrial metabolism. These observations could have some implications for the therapy of cancer, and for the design of combined strategies that act on antioxidant defences of the neoplastic cell.

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Pathophysiology of mitochondrial cell death control

Cited by 42 publications

References 41 publications

Calcium and apoptosis: facts and hypotheses

Calcium and apoptosis: facts and hypotheses

Brain Mitochondria Are Primed by Moderate Ca2+ Rise upon Hypoxia/Reoxygenation for Functional Breakdown and Morphological Disintegration

Apoptosis-resistant phenotype in HL-60-derived cells HCW-2 is related to changes in expression of stress-induced proteins that impact on redox status and mitochondrial metabolism

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