The mitochondrial permeability transition and the calcium, oxygen and pH paradoxes: one paradox after another.

21 See article by Ban et al. [3] (pages 556 –567) in this [3] address two hypotheses. The first is that Ca overload 21 issue. causes futile energy-dissipating mitochondrial Ca cy21 cling. This cycling involves mitochondrial Ca uptake 21 21 In the calcium paradox, Ca -free incubation produces through the mitochondrial Ca uniporter driven by the 1 1 Na loading of cardiac myocytes largely mediated by Na mitochondrial membrane potential (Dc ) and mitochonm 21 21 21 21 influx via L-type Ca channels. Subsequent exposure to drial Ca release by the mitochondrial Na /Ca ex21 1 1 21 normal extracellular Ca activates sarcolemmal Na / changer. Since mitochondrial Na /Ca exchange cata21 1 Ca exchange operating in the reverse mode. As a lyzes the electrogenic interchange of three Na for one 21 21 21 consequence, cytosolic free Ca rapidly increases causing Ca [7], both the uptake and release of Ca dissipate 21 an abrupt and apparently irreversible contracture of the Dc . Support for Ca cycling as the basis for mitom myocytes [1]. The calcium paradox has many parallels to chondrial depolarization in the calcium paradox comes the oxygen paradox of anoxia / reoxygenation and isfrom observations by Ban et al. [3] that ruthenium red, an 1 21 chemia / reperfusion injuries where Na loading occurs inhibitor of the electrogenic mitochondrial Ca uniporter 21 1 during anoxia / ischemia, which is followed by Ca over[8], and CGP-37157, an inhibitor of mitochondria Na / 21 load and irreversible contracture after reoxygenation / reCa exchange [9], both block mitochondrial depolarizaperfusion [2]. tion, NAD(P)H oxidation, and cellular ATP depletion after 21 The interesting and provocative paper by Ban et al. in Ca repletion. Thus, blockade of either mitochondrial 21 this issue of Cardiovascular Research [3] addresses mitoCa uptake or release is sufficient to prevent mitochonchondrial changes occurring during the calcium paradox. drial depolarization. 21 21 21 After Ca repletion following a Ca -free incubation, An alternate hypothesis is that mitochondrial Ca mitochondria of isolated guinea pig cardiac myocytes overloading causes onset of the mitochondrial permeability depolarized completely after a delay of 60–90 s. This transition (MPT). The MPT occurs when a very high event was accompanied by oxidation of mitochondrial conductance permeability transition (PT) pore opens in the NAD(P)H and hydrolysis of ATP, the latter measured mitochondrial inner membrane (reviewed in Ref. [10]). 21 21 indirectly by an increase of free Mg . Mg forms a This pore conducts solutes of molecular weight up to 1500 21 chelate with ATP but not ADP or AMP and thus free Da. Increased Ca and generation of reactive oxygen 21 Mg increases and decreases as ATP hydrolysis and species promote PT pore opening, which in turn causes resynthesis occur in models of anoxia / reoxygenation [4,5]. mitochondrial depolarization, large amplitude mitochonTaken together, the findings of Ban et al. [3] signify a drial swelling and uncoupling of oxidative phosphorylamassive uncoupling of oxidative phosphorylation. Such tion. Cyclosporin A at nanomolar concentrations inhibits uncoupling represents a devastating metabolic disruption the MPT. Ban et al. [3] found that cyclosporin A at a since uncoupled mitochondria not only fail to synthesize concentration of only 200 nM blocked mitochondrial ATP but also actively hydrolyze ATP. This cellular state of depolarization, NAD(P)H oxidation and cellular ATP 21 affairs is worse than having no mitochondria at all [6]. depletion after Ca repletion, implicating that PT pore Why does mitochondrial uncoupling occur? Ban et al. opening is the basis for mitochondrial uncoupling in the calcium paradox. A role for PT pore opening in the calcium paradox, however, would seem to be contradicted *Tel.: 11-919-966-5507; fax: 11-919-966-1856. 21 E-mail address: [email protected] (J.J. Lemasters) by the effect of CGP-37157. By blocking Ca efflux