379 Molecular and Cellular Biochemistry 184: 379–391, 1998. © 1998 Kluwer Academic Publishers. Printed in the Netherlands. Mitochondrial function as a determinant of recovery or death in cell response to injury Fabio Di Lisa 1 and Paolo Bernardi 2 CNR Unit for the Study of Biomembranes and the Departments of 1 Biological Chemistry and 2 Biomedical Sciences, University of Padova, Viale G. Colombo 3, 1-35121 Padova, Italy Abstract Many pathological conditions can be the cause or the consequence of mitochondrial dysfunction. For instance anoxia, which is initiated by a critical reduction of oxygen availability for mitochondrial oxidations, is followed by a wide variety of mitochondrial alterations. A crucial role in the evolution of cell injury is to be attributed to the direction of operation of the F 0 F 1 ATPase, which may turn mitochondria into the major consumers of cellular ATP in the futile attempt to restore the proton electrochemical gradient. On the other hand, functional mitochondria can paradoxically accelerate or exacerbate cell damage. This concept is particularly relevant for the ischemic myocardium. Indeed, inhibition of the respiratory chain or addition of uncouplers of oxidative phosphorylation can both limit the extent of enzyme release in the intact heart and prevent the onset of irreversible morphological changes in isolated myocytes. From studies on different tissues in a variety of pathological conditions a general consensus emerges on the role of intracellular Ca 2+ overload as a pivotal link between cellular alterations and mitochondrial dysfunction. Oxidative phosphorylation is reduced by a massive mitochondrial uptake of Ca 2+ , resulting in a vicious cycle whereby the reduced ATP availability is followed by a failure of the mechanisms which extrude Ca 2+ from the sarcoplasm. In addition, the rise in [Ca 2+ ] i could promote opening of the cyclosporin-sensitive mitochondrial permeability transition pore, leading to a sudden ∆ψ m dissipation. Here, we review the changes in intracellular and intramitochondrial ionic homeostasis occurring during ischemia and reperfusion. In particular, we evaluate the potential contribution of the permeability transition pore to cellular damage and discuss the mechanisms which can determine the cellular fate from a mitochondrial point of view. (Moll Cell Biochem 184: 379–391, 1998) Key words: myocytes, ischemia-reperfusion, hypoxia, cyclosporin, membrane permeability, channels exacerbate cell damage. For instance, as discussed in the following Sections, inhibition of the respiratory chain or addition of uncouplers of oxidative phosphorylation limit the extent of enzyme release in different models of myocardial damage such as post-ischemic reperfusion and calcium paradox [1, 2]. On the other hand, under pathological conditions not only mitochondria cease to be the major ATP producers of the cell: they can also become its major con- sumers owing to the hydrolytic activity of the F 0 F 1 ATPase [3–5]. This inverse operation of the mitochondrial ATPase could also precipitate other harmful conditions, and cause massive ATP hydrolysis in the futile attempt to restore the proton electrochemical gradient ( ∆μ ∼ H) collapsed by the opening of a proton conductive pathway. Address for offprints: Fabio Di Lisa and Paolo Bernardi, CNR, Unit for the Study of Biomembranes, Viale G. Colombo 3, 1-35121 Padova, Italy Introduction Cell injury is a perturbation of cellular vital processes which initiates a series of events leading to functional and structural alterations. In the most severe cases cell death is the final outcome, but cell recovery is possible upon early interruption of the damaging condition. This means that a point of no return exists which can only be defined after the fact. Indeed, we still ignore the primary molecular mechanisms which make the injury irreversible. It is quite obvious that maintenance of mitochondrial function is essential for cell survival, and that its complete loss inevitably leads to cell death. However, a number of observations indicate that mitochondria can accelerate or