Publisher Summary The classification of cell death can be based on morphological or biochemical criteria or on the circumstances of its occurrence. Currently, irreversible structural alteration provides the only unequivocal evidence of death; biochemical indicators of cell death that are universally applicable have to be precisely defined and studies of cell function or of reproductive capacity do not necessarily differentiate between death and dormant states from which recovery may be possible. It has also proved feasible to categorize most if not all dying cells into one or the other of two discrete and distinctive patterns of morphological change, which have, generally, been found to occur under disparate but individually characteristic circumstances. One of these patterns is the swelling proceeding to rupture of plasma and organelle membranes and dissolution of organized structure—termed “coagulative necrosis.” It results from injury by agents, such as toxins and ischemia, affects cells in groups rather than singly, and evokes exudative inflammation when it develops in vivo. The other morphological pattern is characterized by condensation of the cell with maintenance of organelle integrity and the formation of surface protuberances that separate as membrane-bounded globules; in tissues, these are phagocytosed and digested by resident cells, there being no associated inflammation.

Cell death : the significance of apoptosis

Opening of the Mitochondrial Permeability Transition Pore Causes Depletion of Mitochondrial and Cytosolic NAD+and Is a Causative Event in the Death of Myocytes in Postischemic Reperfusion of the Heart

The mitochondrial permeability transition pore is a high conductance channel whose opening leads to an increase of mitochondrial inner membrane permeability to solutes with molecular masses up to ≈ 1500 Da. In this review we trace the rise of the permeability transition pore from the status of in vitro artifact to that of effector mechanism of cell death. We then cover recent results based on genetic inactivation of putative permeability transition pore components, and discuss their meaning for our understanding of pore structure. Finally, we discuss evidence indicating that the permeability transition pore plays a role in pathophysiology, with specific emphasis on in vivo models of disease.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1742-4658.2006.05213.x

The mitochondrial permeability transition from in vitro artifact to disease target

A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury.

MANY laboratory and clinical observations have implicated altered lipid metabolism as a contributor to membrane dysfunction, electrophysiological derangements, malignant arrhythmia, and cellular injury in ischemic myocardium. Amphipathic metabolites, moieties with both hydrophobic and hydrophilic properties, are capable of exerting deleterious effects on biological membrane systems through multiple mechanisms. Because of their structure, amphiphiles can alter membrane function by inserting into the phospholipid bilayer, and, under some conditions, can act as detergents with resultant dissolution of membrane constituents including cholesterol and phospholipids. This selective review will consider the metabolism of fatty acids, fatty acid esters, and phospholipid catabolites which increase in ischemic myocardium and have been implicated as biochemical mediators of membrane dysfunction. Two reviews dealing with the biophysics of lipid alterations in membranes and alterations of carbohydrate and fatty acid metabolism during ischemia have been published recently (Liedtke, 1981; Katz and Messineo, 1981).

BRIEF REVIEWS Amphipathic Metabolites and Membrane Dysfunction in Ischemic Myocardium

The effects of 5 mM potassium cyanide (KCN) on creatine phosphokinase (CPK) release and cellular morphology were studied. Rat hearts were perfused with substrate-deficient media gassed with O2 or N2 (O2 medium, N2 medium) at 37 C, and effluent was collected for creatine phosphokinase analysis. Tissue fixation was with glutaraldehyde for light and electron microscopy. Experiments included the following: a) continuous perfusion with O2- or N2-medium in the presence of KCN; b) 45 or 60 minutes of perfusion with N2-medium followed by O2-medium for 15 or 180 minutes, respectively; c) 45 minutes of perfusion with N2-medium with KCN added 15 minutes before reoxygenation with O2-medium plus KCN; (4) 60 minutes of N2-medium plus KCN followed by O2-medium plus KCN for 180 minutes; d) as a control for irreversible injury, 21 minutes of perfusion with calcium-free O2-medium followed by 2.5 mM calcium-O2-medium ("calcium paradox"). The following results were seen: a) Initial CPK release occurred about 30 minutes later from hearts perfused with O2-medium plus KCN than from hearts perfused with N2-medium plus KCN. b) Upon reoxygenation after either 45 or 60 minutes of anoxia, hearts had a sudden peak of oxygen-induced CPK release. Most irreversibly injured cells were massively swollen and had sarcolemmal defects and contraction bands. Reversibly injured cells in the same hearts resembled normal myocardium. A previously unrecognized third population of cells is described. These cells were characterized by contraction bands but were not swollen, had intact sarcolemma, and contained both normal and damaged mitochondria with intramatrical calcium accumulation granules. It could not be determined if these cells were reversibly injured or in an early stage of irreversible injury. c) KCN added 15 minutes before reoxygenation of hearts after 45 minutes of anoxia inhibited the sudden peak of oxygen-induced CPK release but not a slow sustained release. Small to moderate numbers of cells in these hearts contained contraction bands. d) After 60 minutes, KCN completely inhibited both oxygen-induced CPK release and contraction band formation. e) Addition of calcium to calcium-free hearts caused both massive CPK release and contraction band formation. It is concluded that: the beginning of CPK release from oxygenated KCN-inhibited hearts requires about 30 minutes longer than from anoxic hearts; KCN can inhibit both oxygen-induced CPK release and contraction bands in irreversibly injured rat myocardial cells; sudden contracture of myocardial cells as occurs in the calcium paradox can result in massive CPK release; contraction bands occur in nonswollen cells, hence contraction bands can occur independently of massive cell swelling or membrane rupture. It is postulated that there may be two stages of irreversible myocardial injury; a) loss of control of contraction and b) progressive loss of mitochondrial and membrane integrity.

Oxygen-induced enzyme release after irreversible myocardial injury. Effects of cyanide in perfused rat hearts.

Irreversible injury was produced in Langendorf-perfused rat hearts by 60 minutes of hypoxic, substrate-free perfusion at 37 C. Upon reoxygenation, hearts suddenly released large amounts of creatine phosphokinase (CPK) and over 60% of cells contained contraction bands and appeared irreversibly injured by light and electron microscopic criteria. Ten percent polyethylene glycol (PEG) or mannitol (420 mOsmol/liter) prevented or reduced swelling of rat heart slices incubated in vitro in the cold or under anoxic conditions. Both PEG and mannitol inhibited oxygen-induced CPK release after 60 minutes of hypoxia. Cells from protected hearts contained contraction bands but remained structurally intact. The results of this study provide evidence that cell swelling may play an important role in the pathogenesis of oxygen-induced enzyme release and irreversible myocardial cell injury.

Cellular swelling and irreversible myocardial injury. Effects of polyethylene glycol and mannitol in perfused rat hearts.

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Oxygen-induced enzyme release after irreversible myocardial injury. Effects of cyanide in perfused rat hearts.

Cellular swelling and irreversible myocardial injury. Effects of polyethylene glycol and mannitol in perfused rat hearts.