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Divisions of 1Cardiology and 2Clinical Pharmacology, Department of Medicine, 3Department of Pharmacology, and 4Department of Oral Diagnosis, School of Dental Medicine, Case Western Reserve University, and 5Medical and 6Pathology and Laboratory Medicine Services, Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio 44106
Submitted 11 April 2003 ; accepted in final form 18 February 2004
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ABSTRACT |
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cytochrome c; oxygen radicals; phospholipids
Cytochrome oxidase is an integral membrane complex of 13 peptide subunits (31) that requires catalytic subunits (31), regulatory and structural subunits (3, 31), and a cardiolipin-rich inner mitochondrial membrane environment (53, 66) for activity. Cardiolipin is an oxidatively sensitive phospholipid present only in mitochondria (26). The decrease in oxidation through cytochrome oxidase after ischemia does not result from functional inactivation of a peptide subunit (39) but probably occurs secondary to the loss of cardiolipin (37, 49).
Mitochondria contribute to oxidative damage in the rabbit heart during reperfusion (2) after periods of ischemia that deplete cardiolipin and decrease the rate of oxidative phosphorylation through cytochrome oxidase in SSM (37, 39). The extent of mitochondrial injury that occurs during reperfusion vs. inhibition that results from ischemia alone remains unclear. The present study found that reperfusion did not lead to additional defects in the distal electron transport chain. The decreased contents of cardiolipin and cytochrome c, as well as decreased oxidation through cytochrome oxidase, persist but do not worsen during reperfusion in SSM. A decrease in cardiolipin content predisposes to mitochondrial release of cytochrome c (45, 55, 58), also potentially decreasing mitochondrial respiration and activating programmed cell death pathways (8, 22). On the basis of results in membrane systems, a persistent decrease in cardiolipin content during reperfusion is expected to predispose toward the release of cytochrome c (21, 45) and depress respiration through cytochrome oxidase via a direct effect on cytochrome oxidase activity (14, 53, 66) and, perhaps, indirectly via the decreased content of cytochrome c (12). A decrease in electron flux through cytochrome oxidase, in turn, is likely to enhance the production of reactive oxygen species from more proximal redox centers in the electron transport chain (13, 52). Thus the inhibition of the distal electron transport chain that occurs during ischemia can lead to myocyte injury during reperfusion, even in the absence of additional damage to the distal electron transport chain itself. However, the production of reactive oxygen species must be directed away from the inner mitochondrial membrane toward other compartments in the myocyte, because the distal electron transport chain does not sustain additional injury during reperfusion.
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MATERIALS AND METHODS |
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Rabbit heart model of mitochondrial oxidative physiology during ischemia and reperfusion. The isolated, buffer-perfused rabbit heart model was used as previously described (37, 39). All animal protocols were approved by the Institutional Animal Care and Use Committees of the Louis Stokes VA Medical Center. Briefly, New Zealand White rabbits (2–4 kg) were anesthetized with pentobarbital sodium (65 mg/kg iv), and the hearts were rapidly excised and mounted for retrograde perfusion of the coronary circulation with modified Krebs-Henseleit buffer (in mM: 115 NaCl, 4.0 KCl, 2.6 CaCl2, 26 NaHCO3, 1.1 MgSO4, 0.9 KH2PO4, and 5.5 glucose), gassed with 95% O2-5% CO2, pH 7.35–7.45. Hearts were perfused for a 15-min equilibration period. Nonischemic control hearts were removed from the column and immediately processed. The ischemic group underwent 45 min of no-flow ischemia. The reperfusion group was reperfused for 30 min after 45 min of ischemia. Hearts perfused for a total of 60 min as time controls for ischemia displayed hemodynamic and mitochondrial function similar to the nonischemic hearts (37). Release of lactate dehydrogenase from the myocardium was measured in coronary effluent by the fluorometric measurement of NADH consumption during the conversion of pyruvate to lactate (40, 41).
SSM and IFM populations of cardiac mitochondria were isolated according to the method of Palmer et al. (46) except that a modified Chappell-Perry buffer (buffer A; in mM: 100 KCl, 50 MOPS, 1 EDTA, 5 MgSO4·7H2O, and 1 ATP, pH 7.4) was used for mitochondrial isolation (37, 39). All equipment and solutions were kept at 4°C during the isolation process. Briefly, cardiac tissue was finely minced, placed in buffer A containing 0.2% BSA, and homogenized with a Polytron tissue processor for 2.5 s at a rheostat setting of 6.0. The Polytron homogenate was centrifuged at 500 g, the supernatant was saved for isolation of SSM, and the pellet was washed. The combined supernatants were centrifuged at 3,000 g to sediment SSM, washed twice, and suspended in KME (in mM: 100 KCl, 50 MOPS, and 0.5 EGTA). The Polytron pellet was resuspended in buffer A, nagarse was added to a final concentration of 5 mg/g wet wt of tissue, and the suspension was immediately homogenized with a Potter-Elvejhem homogenizer, diluted with buffer A containing 0.2% BSA, and centrifuged at 5,000 g. The pellet was resuspended in buffer A + 0.2% BSA and centrifuged at low speed (500 g) to sediment myofibrillar debris. The pellet was washed, the mitochondria-containing supernatants were combined, and IFM were isolated by centrifugation at 3,000 g. IFM were washed twice and suspended in KME (39).
Oxygen consumption in intact mitochondria was measured using a Clark-type oxygen electrode at 30°C (39). Cytochrome c content was measured as the difference between ferricyanide-oxidized and dithionite-reduced spectra (37, 39). Protein concentrations were measured using the biuret method, with BSA used as the standard (37, 39).
Morphological analysis of the myocardium and isolated mitochondria was performed as previously described (39). Specimens of the left ventricle were initially fixed by immersion in phosphate-buffered triple aldehyde-DMSO (33). Isolated mitochondria were fixed in suspension by addition of an equal volume of phosphate-buffered full-strength Karnovsky's fixative (39, 46). Semithin sections of myocardium were assessed by light microscopy.
Separation, quantification, and characterization of mitochondrial phospholipids, including cardiolipin. Mitochondrial phospholipids were separated, quantified, and characterized according to a previously described experimental approach (38). Briefly, lipids were extracted from mitochondria using the method of Folch et al. (19), with butylated hydroxytoluene added as an antioxidant (38). Lipid classes were serially eluted using solvents of increasing polarity from silica gel columns (28), normal-phase HPLC separation of phospholipids and lysophospholipids was performed (38), and organic phosphate was measured in 2-ml fractions from normal-phase HPLC (38). The limit of detection was 2.5 nmol.
Individual molecular species of cardiolipin were separated using reverse-phase HPLC and characterized by electrospray ionization-mass spectrometry (MS) (38). The cardiolipin-containing fraction was collected from normal-phase HPLC and evaporated under N2, and reverse-phase HPLC was performed as described elsewhere (38) with minor modifications (see Fig. 4 legend). Electrospray ionization-MS was performed using a liquid chromatography-MS instrument (Finnegan, San Jose, CA) in the negative-ion mode. Three scan events were used: 1) 1,000–2,000 mass-to charge ratio (m/z) full-scan MS, 2) data-dependent full-scan MS2 on the most intense ion from the MS full spectrum, 3) data-dependent full-scan MS3 on the most intense ion from the full-scan MS/MS spectrum. The MS2 and MS3 relative collision energy was set to 48%. This data-dependent multistage MS fragmentation was used to characterize the individual molecular species of cardiolipin as they eluted from the reverse-phase HPLC system. Effluent flow for the first 2 min was diverted to waste.
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RESULTS |
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In general, at the ultrastructural level, the cardiomyocytes themselves, whether they were from hearts subjected to ischemia or to ischemia and reperfusion, showed very few alterations (Fig. 1). Sarcolemmas generally were intact. Nuclei consisted largely of euchromatin with a small proportion of marginated heterochromatin. Whether subsarcolemmal or interfibrillar, the mitochondria usually showed a high level of preservation (Fig. 1); the major difference in these organelles was that mitochondria in hearts subjected to ischemia alone showed a decreased matrix density, as previously described (39) (Fig. 1). Reperfusion, however, tended to restore mitochondria to a matrix density closer to that of untreated controls. Cristae were in normal position and configuration. Cells that by light microscopy appeared to have an extracted cytosol actually possessed cytosol that consisted of finely fibrillopunctate, modestly dense material of unknown nature. In certain cardiomyocytes, there was a separation of myofibrils, with the space between them occupied by lakes of small particles of moderate density; some myofibrils appeared truncated. On the basis of their size, these particles are neither glycogen nor ribosomes. These lucent or particulate spaces occasionally contained a membranous profile of a large, empty-appearing vacuole and/or some small lysosomes. In every case, the sarcoplasmic reticulum was disrupted.
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As previously described, oxidative phosphorylation through cytochrome oxidase, with N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) and ascorbate as the substrate, was decreased after 45 min of ischemia in SSM (39). The rate of oxidative phosphorylation and uncoupled respiration, with TMPD-ascorbate as the substrate, did not worsen during reperfusion in SSM (Table 2). The oxidation of TMPD-ascorbate was unaffected by ischemia or reperfusion in IFM (Table 2).
Quantification of phospholipids in SSM and IFM after reperfusion. Mitochondria contained phosphatidylethanolamine, phosphatidylinositol, cardiolipin, and phosphatidylcholine (Table 3). Total phospholipid phosphate was measured in the phospholipid fraction obtained from the silica gel column. The recovery of total phospholipid phosphate as the four individual phospholipids isolated from normal-phase HPLC was excellent in SSM and IFM obtained from reperfused hearts (Table 3). Ischemia decreased the content of cardiolipin in SSM, whereas the content of the remaining phospholipids was unchanged (37). Reperfusion did not lead to a further decrease in the content of cardiolipin in SSM (Table 3). As discussed below, the composition of cardiolipin was also unchanged by reperfusion (Fig. 6). Consistent with the critical importance of cardiolipin content to respiratory function, the rate of oxidation through cytochrome oxidase varied as a function of cardiolipin content (Fig. 7).
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Cardiolipin composition in SSM and IFM after reperfusion. The composition of cardiolipin was studied using reverse-phase HPLC separation of the individual molecular species followed by characterization using electrospray ionization-MS. Figure 6 shows the reconstructed ion chromatograms of the reverse-phase HPLC separation of the molecular species of cardiolipin obtained from SSM and IFM from control hearts and from hearts after 45 min of ischemia with 30 min of reperfusion. Despite the decrease in cardiolipin content in SSM, the composition of cardiolipin was similar in SSM and IFM from control hearts and hearts subjected to ischemia-reperfusion.
The major molecular species of cardiolipin (m/z = 1,448), eluting at a retention time of 8.8–9.1 min, was identified using the collision-induced fragmentation pattern as cardiolipin containing four C18:2 acyl residues (37, 38). Two minor peaks at retention times of 10 and 12 min, present in control samples and samples subjected to ischemia-reperfusion, did not fragment in a fashion consistent with a cardiolipin and remain unidentified (data not shown). The finding of a single, dominant molecular species of cardiolipin is consistent with the observation that linoleic acid comprises >95% of the acyl groups in cardiolipin obtained from control rabbit hearts (37). Reperfusion did not lead to the generation of new molecular species of cardiolipin (Fig. 6). Thus neither SSM, which sustain ischemic damage to cardiolipin (37), nor IFM, which are spared ischemic damage, exhibited alterations in cardiolipin composition after ischemia (37) or ischemia-reperfusion (Fig. 6).
Oxidized cardiolipin (27) was used as a positive control. Oxidized cardiolipin elutes in the cardiolipin peak from normal-phase HPLC and is detectable by reverse-phase HPLC and MS. Oxidized bovine cardiolipin contains a molecular species that elutes in the reverse-phase chromatogram at a retention time of 4–5 min (data not shown). This molecular species peak (m/z = 1,480) fragments in a fashion consistent with a cardiolipin that contains two additional oxygen atoms in acyl residues, suggesting the presence of hydroxy- or peroxy-containing acyl groups (data not shown). Oxidized cardiolipin was not observed in the reverse-phase chromatographic peaks obtained from SSM or IFM from control hearts or hearts subjected to ischemia-reperfusion with use of MS. Oxidized cardiolipin, if present in mitochondrial phospholipids, would have been detected.
Cytochrome content in SSM and IFM during reperfusion. The content of cytochrome c decreased in SSM after 45 min of ischemia, as previously described (37, 39). Cytochrome c content was decreased by 35% after ischemia in SSM and remained decreased during 30 min of reperfusion: 0.17 ± 0.01 nmol/mg protein in control (n = 6), 0.10 ± 0.01 nmol/mg protein in ischemia (n = 10, P < 0.01 vs. control), and 0.13 ± 0.03 nmol/mg protein in reperfusion [n = 6, P < 0.05 vs. control and P = not significant (NS) vs. ischemia]. In support of the key role of cardiolipin in retention of cytochrome c by mitochondria (45), in the present study the content of cytochrome c correlated with the cardiolipin content in SSM (Fig. 8).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Cytochrome oxidase activity requires a cardiolipin-rich environment in the inner mitochondrial membrane (53, 66). A decrease in cardiolipin content or loss of unsaturated acyl groups decreases cytochrome oxidase activity in isolated membrane systems (14, 53, 66). Cytochrome oxidase enzyme activity is highly dependent on cardiolipin content in in vitro systems (1, 68). In our in situ model of ischemia and reperfusion, the rate of oxidation through cytochrome oxidase also varied as a function of cardiolipin content (Fig. 7). Cardiolipin content was also decreased after global ischemia and reperfusion in the isolated perfused rat heart (49) and after regional ischemia in the canine heart (32).
We examined the composition of cardiolipin after reperfusion on the basis of the profile of individual molecular species. The composition of cardiolipin after reperfusion was similar to that observed before and at the end of ischemia (Fig. 6). Total phospholipid phosphate was accounted for by the sum of the four measured phospholipids, making an increase in the content of lysocardiolipin or the formation of other phosphorus-containing lipids during reperfusion unlikely. The absence of lysophospholipids, especially dilysocardiolipin, during reperfusion makes hydrolysis of cardiolipin by phospholipase A2 an unlikely mechanism of cardiolipin loss.
The absence of oxidative damage to cardiolipin during ischemia or reperfusion initially seemed to represent a paradox. Cardiolipin is highly enriched in oxidatively sensitive acyl groups containing 90–95% linoleic acid (C18:2) (1, 37). During ischemia, reactive oxygen species are generated by mitochondria, despite the low oxygen tension (5, 34). In the intact heart, oxidation of cardiolipin can lead to the direct destruction of cardiolipin (24, 44) or to covalent cardiolipin-protein complexes that render cardiolipin undetectable as a phospholipid (60). Thus oxidative processes remain a potential mechanism of the ischemia-induced decrease in cardiolipin content in SSM. The absence of additional decreases in cardiolipin content during early reperfusion suggests that oxidative processes during reperfusion are directed away from the mitochondrial inner membrane (see below).
Persistent decreases in cytochrome oxidase activity can lead to oxidative injury during reperfusion. Although cytochrome oxidase itself does not produce reactive oxygen species (64), the enzyme complex has an important antioxidant role by modulating local oxygen content and the redox status of upstream electron transport chain complexes I and III (31, 48). Electron flow through cytochrome oxidase is under respiratory control, coupled to inner membrane potential via proton transport, and is independent of respiratory control ("uncoupled") (31, 48). Uncoupled electron flow occurs via proton "slip" within cytochrome oxidase, permitting electron flow through cytochrome oxidase independent of membrane potential (31, 48). The uncoupled electron flow decreases the prooxidant state of mitochondria by decreasing the relative reduction of proximal redox centers in complexes I and III. A less reduced state of complexes I and III, in turn, decreases the electron "leak" from these complexes, which generates reactive oxygen species (31, 48). Conversely, the inhibition of cytochrome oxidase enhances oxidative cell killing from the electron transport chain (13, 52). The persistent decrease in oxidation through cytochrome oxidase during reperfusion predisposes to the generation of reactive oxygen species. Not surprisingly, reperfusion after periods of ischemia that decrease respiration through cytochrome oxidase in SSM (37, 39) results in mitochondria-derived oxidant production and oxidative myocyte injury in the isolated perfused rabbit heart (2). Thus the decrease in cytochrome oxidase activity during reperfusion provides a possible link between ischemic damage to the distal electron transport chain and mitochondria-derived oxidative injury during reperfusion.
The suggestion that mitochondria generate oxidative damage to the myocyte during reperfusion while sustaining only minimal additional oxidative damage themselves initially appears to represent a paradox. Complexes I and III are the sites of oxidant production during ischemia and reperfusion (2, 61). The site of electron leak from complex I is the NADH dehydrogenase portion of the complex (62) located on the matrix side of the inner mitochondrial membrane (23). Thus oxidant production from complex I is most likely directed into the mitochondrial matrix and should lead to mitochondrial damage or be detoxified by matrix antioxidant enzyme systems (36). In contrast, complex III can directly reduce molecular oxygen to form superoxide (·O2–) at a site located on the outside face of the inner mitochondrial membrane [i.e., the Qo site (15, 43)]. This site has been shown to direct oxidants toward the intermembrane space, apparently away from the inner mitochondrial membrane and toward nonmitochondrial compartments of the myocyte (20, 25). Superoxide produced from the Qo site can even be released from mitochondria into the cytosol via the voltage-dependent anion channel (25), providing a potential mechanism for the directed release of oxidants produced from complex III into the myocyte and away from mitochondria. Ischemia leads to damage to complex III (35), probably increasing the production of reactive oxygen species from this site in the electron transport chain (5). As discussed above, the production of superoxide by complex III should be enhanced by the downstream inhibition of cytochrome oxidase. Thus the Qo site may indeed be the locus for the increased production of reactive oxygen species, which leads to oxidative myocyte damage but not to further damage to the distal electron transport chain.
Ischemia leads to the loss of cytochrome c from mitochondria (6–8, 29, 30, 39). Cytochrome c is detected in the cytosol after 30 min of ischemia in the rabbit heart (17) and in the rat heart as well (8). The content of cytochrome c decreases in SSM at 30 and 45 min of ischemia, concomitant with cardiolipin loss (37). In IFM, cytochrome c content is preserved at 30 min of ischemia (37) but is modestly decreased at 45 min of ischemia (see above). SSM exhibit a greater tendency to release cytochrome c in vitro (47) and sustain a more rapid progression of ischemic damage in situ (39), including the loss of cytochrome c (37, 39). SSM, intrinsically more sensitive to release of cytochrome c in the setting of elevated external calcium (47), also reside in a region of the myocyte, the subsarcolemmal space, that appears to undergo the greatest deleterious shifts in electrolyte concentrations during ischemia (29). Thus SSM are poised to be the subpopulation of cardiac mitochondria that are likely to release a substantial amount of cytochrome c during ischemia.
A decrease in cardiolipin content can predispose to the loss of cytochrome c from mitochondria. Cardiolipin provides binding sites on the inner membrane for cytochrome c (9, 51, 55, 58), with electron paramagnetic resonance evidence of partial insertion of cytochrome c into the membrane at cardiolipin-containing sites (56, 58). The binding of cytochrome c to membrane systems depends on the content and composition of cardiolipin (55, 57). A decrease in cardiolipin content or the oxidative modification of cardiolipin diminishes the affinity of cytochrome c for cardiolipin-containing membranes (55, 57). Cardiolipin oxidation or depletion delocalizes cytochrome c from the inner mitochondrial membrane (45, 57), and then cytochrome c release permeabilizes the outer mitochondrial membrane (45). In the present study, the content of cytochrome c correlated with the cardiolipin content in SSM (Fig. 8). However, the decrease in cytochrome c content that occurs in IFM, despite the preserved cardiolipin content, clearly shows that ischemia leads to some loss of cytochrome c without cardiolipin depletion. Future studies are required to understand the potential contribution of cardiolipin depletion to the release of cytochrome c during myocardial ischemia.
Mitochondrial permeability transition appears to contribute to myocardial injury during ischemia (8) and reperfusion as well (11). In apparent contradiction to this observation in the myocardium, the morphological and biochemical study of isolated mitochondria suggests that mitochondria are largely intact after ischemia (37, 39) as well as after early reperfusion in the present study. These observations suggest that at least a component of permeability transition observed in situ in the heart may occur secondary to transient, reversible opening of the transition pore (67). The "pore open probability" for mitochondria in the ischemic or reperfused myocardium probably represents a real-time integration of chemical stresses that favor opening of the permeability transition pore (calcium and reactive oxygen species) in contrast to countervailing processes (high-energy phosphates, magnesium, and reduced sulfhydryl groups) that favor pore closure. The use of relaxing buffers with calcium chelators, magnesium, and low temperature during mitochondrial isolation will favor the closure of permeability transition pores during the isolation process in mitochondria that have undergone "flickering," but not irreversible pore opening. In fact, the preserved recovery of mitochondria from ischemic myocardium (35–37, 39) argues in favor of this proposal. In situ, the intracellular milieu of the ischemic or reperfused cardiomyocyte may lead to additional degradation of mitochondrial function (29), including probably transient opening of the permeability transition pore (8).
Brief periods of myocardial ischemia (
15 min) result in reversible postischemic contractile dysfunction ("stunning") and the absence of myocyte death (18). As the duration of ischemia progresses to 30 and 45 min, the rate of oxidation through cytochrome oxidase decreases in intact SSM (39). The more prolonged periods of ischemia result in myocyte death during ischemia and reperfusion. Mechanisms of mitochondria-derived myocyte damage include production of reactive oxygen species, onset of mitochondrial permeability transition (8, 67), and apoptosis triggered by mitochondrial loss of cytochrome c (8, 36). Reperfusion after 30 min of ischemia results in mitochondria-derived oxidative myocyte damage in the isolated rabbit heart (2). Ischemic injury to the distal electron transport chain, with a decrease in the contents of cardiolipin and cytochrome c and a decrease in respiration through cytochrome oxidase, may contribute to enhanced oxidative injury and activation of programmed cell death pathways that become more evident during reperfusion (2, 10). Ischemic damage to the distal electron transport chain emerges as a potential link between ischemia and the mitochondria-driven myocyte injury that occurs during reperfusion in the isolated rabbit heart.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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-ketoglutarate dehydrogenase. Proc Natl Acad Sci USA 96: 6689–6693, 1999.This article has been cited by other articles:
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