On the involvement of a cyclosporin A sensitive mitochondrial pore in myocardial reperfusion injury

Duchen, Michael R.; McGuinness, O.M.; Brown, Leslie; Crompton, Martin

doi:10.1093/cvr/27.10.1790

Cited by 281 publications

(167 citation statements)

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“…4A and 5, A and B). Previously, it has been shown that a 12% change in fluorescence signal of JC-1 reflects a 10-mV change in the membrane potential (41). Therefore, the increases in JC-1 fluorescence at 12, 18, and 24 h of cisplatin exposure in RPTC correspond to ⌬⌿ m of Ϫ180, Ϫ230, and Ϫ270 mV, respectively.…”

Section: Resultsmentioning

confidence: 86%

Protein Kinase C-α and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na+ Transport, and Cisplatin-induced Apoptosis in Renal Cells

Nowak

2002

Journal of Biological Chemistry

250

204

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Section: Resultsmentioning

confidence: 86%

Protein Kinase C-α and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na+ Transport, and Cisplatin-induced Apoptosis in Renal Cells

Nowak

2002

Journal of Biological Chemistry

250

204

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“…5C; Schinder et al 1996;Nieminen et al 1996;Castilho et al 1998;Keelan et al 1998). A similar process may take place in the heart following reperfusion after an ischaemic episodeagain conditions in which mitochondrial Ca¥ loading will be combined with oxidative stress, leading to MPT and cell death (Duchen et al 1993a;Griffiths & Halestrap, 1995). Why should the cell place such fundamental decisions about life and death in the hands of the mitochondrial interlopers?…”

Section: Modulation Of Spatiotemporal [Ca¥]c Signals By Mitochondriamentioning

confidence: 99%

Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signalling and cell death

Duchen

1999

The Journal of Physiology

570

428

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Since the award of the 1978 Nobel prize for Chemistry to Peter Mitchell for his formulation of the chemiosmotic theory of oxidative phosphorylation (Mitchell & Moyle, 1967), most physiologists have regarded mitochondria as 'solved'. They have been perceived as divorced from those aspects of physiology that are deemed exciting and significant, and dismissed as boring structures whose sole function is to manufacture ATP unobtrusively and on demand, subservient to the energetic demands of the cell. This essay was unwittingly prompted by a colleague who sat down next to me at coffee one morning, after giving an undergraduate lecture on basic cell biology and commented 'You work on mitochondria, don't you? Why are they interesting? What should I tell the students?' Over the last few years, mitochondria have re-emerged into the spotlight of scientific scrutiny after many years in the wings, as unfamiliar roles are attributed to them that even Peter Mitchell would probably never have imagined (see also Miller, 1998). 'The biggest picture?'Oxygen is necessary for life -but only because our mitochondria use it to generate ATP. Thought to be derived from prokaryotic micro-organisms which evolved a symbiotic relationship with their eukaryotic hosts (for review, see Margulis, 1996 and see Gray, 1998), mitochondria are our primary consumers of oxygen, and it could be argued that the mitochondrial requirement for oxygen delivery has driven the evolution of the respiratory and cardiovascular systems. Mitochondria, despite all that follows here, are primarily ATP generators. This is far from trivial: ATP is the major currency in the cellular economy, required to drive by far the majority of energy-requiring reactions in all living things, from bacteria and plants to man. It is necessary for the phosphorylation reactions that modulate so many fundamental cellular processes. It may be stored and used as a (neuro)transmitter, and it controls the activity of several classes of ion channel (such as the ATP-sensitive K¤ (KATP) channel, the calcium release channel of sarcoplasmic reticulum and voltage-gated calcium channels). Mitochondria also take up calcium, and are functionally tightly integrated into mechanisms of cellular calcium signalling, and this will provide a major focal point below. It is also often forgotten that mitochondria house a number of critically important biochemical processes quite distinct and separate from energy metabolism -key enzymes involved in haemoglobin and steroid synthesis, for example, and even the carbonic anhydrase needed to make gastric acid.

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“…Mitochondrial dysfunction due to a permeability transition can precipitate a bioenergetic crisis with ATP depletion and Ca 2ϩ dysregulation (2)(3)(4). On the other hand, mitochondria can release proteins that cause cell death through both caspase-dependent and caspase-independent mechanisms (5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

Early resistance to cell death and to onset of the mitochondrial permeability transition during hepatocarcinogenesis with 2-acetylaminofluorene

Klöhn

Soriano

Irwin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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A hallmark of tumorigenesis is resistance to apoptosis. To explore whether resistance to cell death precedes tumor formation, we have studied the short-term effects of the hepatocarcinogen 2-acetylaminofluorene (AAF) on liver mitochondria, on hepatocytes, and on the response to bacterial endotoxin lipopolysaccharide (LPS) in albino Wistar rats. We show that after as early as two weeks of AAF feeding liver mitochondria developed an increased resistance to opening of the permeability transition pore (PTP), an inner membrane channel that is involved in various forms of cell death. Consistent with a mitochondrial adaptive response in vivo, (i) AAF feeding increased the expression of BCL-2 in mitochondria, and (ii) hepatocytes isolated from AAF-fed rats became resistant to PTP-dependent depolarization, cytochrome c release, and cell death, which were instead observed in hepatocytes from rats fed a control diet. AAF-fed rats were fully protected from the hepatotoxic effects of the injection of 20 -30 g of LPS plus 700 mg of D-galactosamine (D-GalN) ؋ kg ؊1 of body weight, a treatment that in control rats readily caused a large increase of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells in liver cryosections and release of alanine and aspartate aminotransferase into the bloodstream. Treatment with LPS and D-GalN triggered cleavage of BID, a BCL-2 family member, in the livers of both control-and AAF-fed animals, whereas caspase 3 was cleaved only in control-fed animals, indicating that the mitochondrial proapoptotic pathway had been selectively suppressed during AAF feeding. Phenotypic reversion was observed after stopping the carcinogenic diet. These results underscore a key role of mitochondria in apoptosis and demonstrate that regulation of the mitochondrial PTP is altered early during AAF carcinogenesis, which matches, and possibly causes, the increased resistance of hepatocytes to death stimuli in vivo. Both events precede tumor formation, suggesting that suppression of apoptosis may contribute to the selection of a resistant phenotype, eventually increasing the probability of cell progression to the transformed state.

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On the involvement of a cyclosporin A sensitive mitochondrial pore in myocardial reperfusion injury

Cited by 281 publications

References 0 publications

Protein Kinase C-α and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na+ Transport, and Cisplatin-induced Apoptosis in Renal Cells

Protein Kinase C-α and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na+ Transport, and Cisplatin-induced Apoptosis in Renal Cells

Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signalling and cell death

Early resistance to cell death and to onset of the mitochondrial permeability transition during hepatocarcinogenesis with 2-acetylaminofluorene

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