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Published as doi: 10.1096/fj.05-4535fje.
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(The FASEB Journal. 2006;20:1543-1545.)
© 2006 FASEB

Reversal of mitochondrial defects before ischemia protects the aged heart

Edward J. Lesnefsky*,§,1, DingChao He*, Shadi Moghaddas* and Charles L. Hoppel{dagger},{ddagger},§

Departments of Medicine (Divisions of
* Cardiology and

{dagger} Clinical Pharmacology) and

{ddagger} Pharmacology, Case Western Reserve University and Medical Service,

§ Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, USA

1Correspondence: Cardiology Section, Medical Service 111(W), Louis Stokes VA Medical Center, 10701 East Blvd., Cleveland, OH 44106, USA. E-mail: EXL9{at}cwru.edu

ABSTRACT

Myocardial injury is increased in the aged heart during ischemia and reperfusion. Aging decreases oxidative metabolism in interfibrillar mitochondria (IFM) located between the myofibrils. We asked whether reversal of aging defects in IFM before ischemia would decrease injury in the aged heart following ischemia and reperfusion. Treatment with acetylcarnitine (AcCN) increases the activity of cytochrome oxidase in the aged heart. Aged (24 months) and adult (6 months) Fischer 344 rats were treated with AcCN (300 mg/kg i.p. 3 h before excision of the heart) or served as controls. AcCN restored oxidative phosphorylation and the activity of complexes III and IV in IFM from aged hearts to rates present in adults. Isolated hearts underwent 25 min global ischemia and 30 min reperfusion without additional treatment. Contractile recovery during reperfusion improved in hearts from AcCN-treated aged rats compared to aged controls and were similar to adults in recovery. AcCN-treated aged hearts sustained less damage, indicated by decreased lactate dehydrogenase (LDH) release during reperfusion. AcCN treatment did not alter functional recovery or LDH release in adults. Restoration of mitochondrial function in the aged heart before ischemia was accompanied by enhanced contractile recovery and decreased tissue injury following ischemia and reperfusion.—Lesnefsky, E. J., He, D., Moghaddas, S., Hoppel, C. L. Reversal of mitochondrial defects before ischemia protects the aged heart.


Key Words: oxidative phosphorylation • reperfusion • cytochrome oxidase • ubiquinol-cytochrome c oxidoreductase (complex III)

THE AGED HEART sustains greater damage during ischemia and reperfusion in experimental models (1 2 3 4 5) and elderly patients (6) . Mitochondria are key participants (1 , 3 , 7) in several mechanisms reported to enhance cardiac injury in the aged heart during ischemia and reperfusion (8) , including oxidative damage (4) , myocyte calcium accumulation (1) , and apoptosis (5) . In the aged heart, ischemic damage to mitochondria is superimposed on preexisting aging-induced defects in mitochondrial oxidative metabolism, (9 10 11) . We evaluated whether an intervention with the potential to improve mitochondrial function in the aged heart before ischemia could decrease myocardial injury during subsequent ischemia and reperfusion.

Cardiac mitochondria exist in two functionally distinct populations: subsarcolemmal mitochondria (SSM) lie beneath the plasma membrane; interfibrillar mitochondria (IFM) are located between the myofibrils (12 13 14) . Aging decreases oxidative function only in IFM whereas SSM are unaffected (13) . Aging decreases the activity of electron transport complexes III (9) and IV (13 , 15) in IFM. If the aging defects in mitochondrial respiration could be diminished or removed, would the aged heart now function as the adult heart and sustain similar damage as the adult heart during ischemia and reperfusion? Treatment with acetylcarnitine was previously reported to restore aging-induced decreases in complex IV activity in the heart (15) . We used acetylcarnitine to ask whether aging-induced decreases in mitochondrial respiration could be improved. In the current study, acetylcarnitine treatment improved rates of oxidative phosphorylation in mitochondria from aged hearts. Acetylcarnitine treatment did not improve contractile recovery or decrease lactate dehydrogenase release following ischemia in the adult heart. Acetylcarnitine treatment to restore mitochondrial function in the aged heart before ischemia provides an experimental model to test the hypothesis that aging-induced mitochondrial defects in respiration are a mechanism of the enhanced damage sustained by the aged heart during ischemia and reperfusion.

MATERIALS AND METHODS

Adult (6 months) and elderly (24 months) male Fisher 344 rats were obtained from the National Institute of Aging colony (Harlan Sprague Dawley, Inc., Indianapolis, IN, USA). Rats received heparin (500 U/kg, i.p.), were anesthetized with pentobarbital (100 mg/kg, i.p.), and hearts were rapidly excised, perfused in the Langendorff mode with modified Krebs-Henseleit buffer (NaCl 115 mM, KCl 4 mM, MgSO4·7H2O 1.1 mM, KH2PO4 0.9 mM, NaHCO3 22 mM, CaCl2·2H2O 2.5 mM), and oxygenated with 92.5% O2 and 7.5% CO2. All animal protocols used were approved by the Animal Care and Use Committees of the Louis Stokes VA Medical Center and Case Western Reserve University. Hearts were perfused for 15 min before 25 min of global 37°C stop-flow ischemia, followed by 30 min reperfusion (2) . Left ventricular systolic pressure, diastolic pressure, developed pressure, and positive and negative dP/dt were measured (2) . Coronary flow was measured every 5 min by timed collection of effluents and lactate dehydrogenase (LDH) activity assayed (2) . Total LDH release during reperfusion was computed as the area under the curve using the parallelogram method based on LDH release (mU/min LDH release x ml/min coronary flow) computed at 5 min intervals during reperfusion (2) .

Acetylcarnitine was administered by i.p. injection (300 mg/kg total dose, 125 mg/ml, neutralized to pH 6.0–7.0 with NaOH). Three hours later the rats were euthanized and the heart removed for either isolation of mitochondria or isolated heart perfusion experiments. Control rats were either untreated (all 6 months and two 24 months) or received i.p. normal saline at pH 6.0–7.0 (three 24 months) in an identical fashion to treated rats. Hemodynamic parameters, including recovery following ischemia, were similar in untreated and i.p. saline vehicle-treated aged hearts (untreated: 32%, 18%; saline treated: 30%, 19%, 20%).

SSM and IFM populations of cardiac mitochondria were isolated as described previously (12 ,13 ,16) . IFM were isolated by incubation of skinned myofibers, obtained after polytron treatment, with 5 mg/g (wet wt) trypsin for 10 min at 4°C. Oxygen consumption by intact mitochondria during state 3 and state 4 respiration was measured in a chamber equipped with a Clark type oxygen electrode (Yellow Springs Instrument Co., Yellow Springs, OH, USA) at 30°C (13) . Uncoupled respiration was measured in the presence of dinitrophenol (0.3 mM) (13 ,14) . Electron transport complex III (decylubiquinol-cytochrome c reductase) was measured as described previously (9) . Mitochondrial cytochrome content was measured as the difference of reduced minus oxidized spectra (9 ,13) . Samples for analysis of complex III and cytochromes were not available from all hearts. Differences between groups were compared by 1-way ANOVA (17) . A P < 0.05 was considered significant.

RESULTS

The protein yield of IFM was decreased in aged hearts as previously observed (13) . Acetylcarnitine did not alter the protein yield of IFM obtained from aged hearts. The yield of SSM was unaltered by age (Fig. 1 ). The maximal rate of ADP-stimulated and dinitrophenol uncoupled oxidation was decreased in IFM from untreated aged hearts compared to untreated adult controls as described previously (13) . Treatment of aged rats with acetylcarnitine increased the maximal rate of oxidative phosphorylation in IFM to rates observed in the adult heart (Table 1 , Fig. 1 ). Respiration in acetylcarnitine-treated aging hearts remained well coupled with unaltered state 4 respiration, respiratory control ratios, and ADP:O ratios (Table 1) .


Figure 1
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  		Figure 1. The protein content and rate of oxidative phosphorylation is decreased in interfibrillar mitochondria (IFM) from the 24 month Fischer 344 heart (aged, n=13) compared with 6 month controls (n=8), whereas subsarcolemmal mitochondria (SSM) remain unaltered by aging. Treatment of 24 month aged rats with acetylcarnitine (AcCN, n=6) (300 mg/kg by i.p. injection) 3 h before isolation of mitochondria from the aged heart did not alter the protein content of IFM but enhanced mitochondrial respiration in SSM and IFM. ±SE; *P < 0.05 vs. same age control; #P < 0.05 vs. 6 months; Glut-glutamate; DHQ-durohydroquinone; TMPD/Asc-N,N,N',N' tetramethyl p-phenylenediamine-ascorbate; respiratory rates expressed as nAO/mg protein/min using 2 mM ADP).


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  		Table 1. Acetylcarnitine treatment of the aged heart restores state 3 respiration and preserves the coupling of oxidative phosphorylation

Aging decreases the activity of complex III in IFM secondary to a defect at the quinol oxidation site with preserved content of subunit peptides, including cytochrome b (9 ,10) . Acetylcarnitine treatment of aged rats restored the activity of complex III in IFM to that present in the adult heart (Table 2 ). Acetylcarnitine increased the content of cytochrome b in IFM (untreated aged: 0.24±0.01 nmol/mg protein, n=9 vs. acetylcarnitine-treated, aged 0.29±0.01, n=5, P < 0.05) as well as in SSM (untreated aged: 0.20±0.02 nmol/mg protein, n=9 vs. acetylcarnitine-treated, aged 0.32±0.01, n=5, P < 0.05). Aging decreases respiration through cytochrome oxidase in intact IFM although cytochrome aa3 content remains unchanged (9 , 10 , 13 , 18) . Acetylcarnitine increased the content of cytochrome aa3 in SSM (untreated aged: 0.62±0.03 nmol/mg protein, n=9 vs. acetylcarnitine-treated, aged 0.77±0.03, n=5, P < 0.05) without a significant increase in IFM (untreated aged: 0.69±0.02 nmol/mg protein, n=9 vs. acetylcarnitine-treated, aged 0.71±0.02, n=5, p=NS).


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  		Table 2. Activity of complex III in mitochondria (mU/min/mg protein)

Adult and aged hearts underwent 25 min of global ischemia followed by 30 min of reperfusion (Table 3 ). Acetylcarnitine treatment did not alter ventricular function measured before ischemia (Table 3) . Diastolic pressure at the end of ischemia was unaltered by acetylcarnitine in adult and aged hearts (Table 3) . Coronary flow before ischemia and during reperfusion was also unchanged by acetylcarnitine (Table 3) . In the aged heart, acetylcarnitine enhanced the recovery of developed pressure (Fig. 2 ) and positive and negative dP/dt (Table 3) , whether measured as absolute magnitude (Table 3) or as a percent of preischemic values (Fig. 2) . In contrast, in the adult heart contractile recovery during reperfusion was unchanged by acetylcarnitine treatment (Table 3) . In acetylcarnitine-treated aged hearts, recovery was similar to the recovery of treated or untreated adult hearts.


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  		Table 3. Acetylcarnitine treatment improves hemodynamic recovery during ischemia and reperfusion selectively in the aged heart


Figure 2
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  		Figure 2. Treatment with acetylcarnitine (AcCN) 3 h before ischemia improved contractile recovery of the aged, but not the adult, heart after 25 min of ischemia and 30 min of reperfusion.

Acetylcarnitine markedly reduced the release of LDH during reperfusion, a marker of myocyte necrosis, in the aged heart (Fig. 3 ). In contrast, acetylcarnitine treatment did not alter LDH release during reperfusion in the adult heart (Fig. 3) . Thus, acetylcarnitine treatment of the aged heart before ischemia improved functional recovery and decreased myocyte cell death following ischemia and reperfusion.


Figure 3
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  		Figure 3. Treatment with acetylcarnitine (AcCN) 3 h before ischemia decreased the release of lactate dehydrogenase, a marker of myocardial damage, during reperfusion in the aged but not the adult heart.

DISCUSSION

Myocardial injury is increased in the aged heart following ischemia and reperfusion (1 , 3 4 5 6) . In the aged heart, IFM exhibit decreased protein yield and reduced rates of oxidative phosphorylation (13) , complex III activity (9 , 10) , and respiration through complex IV (13) . Acetylcarnitine treatment restored the rate of oxidative phosphorylation in IFM from the aged heart whereas protein content remained decreased. Respiration remained tightly coupled after treatment with acetylcarnitine.

When the aged heart was exposed to ischemia and reperfusion after restoration of oxidative phosphorylation, there was less myocardial damage and improved contractile recovery. In contrast, acetylcarnitine treatment had no effect on the extent of myocardial damage or contractile recovery in the adult heart. Thus, acetylcarnitine did not alter mechanisms of ischemic damage common to both the adult and aged hearts. These observations provide strong support for the contribution of aging-related defects in mitochondrial oxidative metabolism to the enhanced damage after ischemia and reperfusion.

Aging decreases the maximal activity of complex III in IFM (9 , 10) despite a preserved content of subunit peptides, including cytochrome b (9) . The aging defect in complex III is located within the quinol oxidation domain of cytochrome b (10) . Acetylcarnitine restores complex III activity in IFM from aged hearts (Table 2) , accompanied by an increase in cytochrome b content. The increase in cytochrome b content following relief of the complex III enzyme defect is in line with cytochrome b as the locus of the aging defect. The increase in cytochrome b content observed in both SSM and IFM after treatment is consistent with an increase in mitochondrial transcription and protein synthesis, perhaps leading to an increased content of complex III, as discussed below.

Aging decreases the rate of oxidative phosphorylation stimulated by TMPD-ascorbate, an electron donor to cytochrome oxidase via cytochrome c in intact IFM (13) (Fig. 1) . Cytochrome oxidase activity measured in permeabilized mitochondria in the presence of exogenous cytochrome c remains decreased in IFM, localizing the defect to the oxidase. Aging did not alter the content of cytochrome aa3 in IFM, indicating a preserved content of cytochrome oxidase (13) . The aging defect was overcome by the addition of exogenous phospholipid liposomes (13) or freezing-thawing combined with detergent solubilization (13) , interventions that alter the membrane environment of the complex. Taken together, these findings strongly suggest that the aging decrease in cytochrome oxidase in IFM occurs due to an altered inner membrane environment of complex IV (8 , 13) despite a preserved content of cardiolipin in IFM (8 , 16) . Acetylcarnitine treatment improved respiration through cytochrome oxidase in both SSM and IFM (Fig. 1) , consistent with previously described results (19) . Improvement appears to have occurred due increases in cytochrome aa3 content, more prominent in SSM, with an increase in cytochrome oxidase content likely contributing to the enhanced TMPD-ascorbate stimulated respiration observed in SSM (Fig. 1) . An acetylcarnitine-mediated improvement in the membrane environment of cytochrome oxidase in IFM that restored respiration in this mitochondrial population (13 , 15 , 20) would account for the restoration of the aging defect in IFM despite the absence of a marked increase in cytochrome aa3 content.

Our working model for increased injury in the aged heart is that the addition of ischemia-induced defects on preexisting aging defects would enhance mitochondrial-derived myocyte injury in the aged heart (8) . Complex III is a major site of free radical production by mitochondria (21 22 23 24) . Aging increases the production of reactive oxygen species (ROS) from complex III in IFM (10) . Myocardial ischemia damages complexes III (11 , 25) and IV (14 , 26) in the adult and aged heart (8) . Mitochondria produce ROS during ischemia (27) and also during reperfusion (28) . Complex III in IFM is a prime source for the enhanced production of ROS during ischemia or reperfusion (8 , 24) .

Aging-induced decreases in complex IV activity in IFM should augment oxidant production. Relative blockage of electron flow through complex IV leads to increased reduction of upstream redox centers in complexes I and III (29) . The aging-induced decrease in respiration through complex IV in IFM (13 , 15 , 30) , coupled with additional decreases due to ischemic damage (14 , 26) , will predispose the aged heart to enhanced oxyradical production. It is reasonable to suppose that restoration of oxidative phosphorylation through complexes III and IV in interfibrillar mitochondria by acetylcarnitine (DHQ respiration, Fig. 1 ) would decrease oxidative damage during ischemia and reperfusion in the aged heart.

Acetylcarnitine has been proposed to improve aging defects in electron transport by two mechanisms. First, acetylcarnitine was proposed to increase the content of cardiolipin (15 , 19 , 20) , a phospholipid present in mitochondria that is required for optimal activity of complex IV (31) . However, despite the aging-related membrane defect in IFM (8 , 13) , aging does not decrease the content of cardiolipin in either SSM or IFM in the aged Fischer 344 rat heart (16) . Second, treatment with acetylcarnitine increases transcription of mitochondrial DNA (mtDNA) in the aged heart in a dose- and time-dependent manner (32) . The optimal response to acetylcarnitine occurs at 3 h and 300 mg/kg, the treatment regimen used in the current study. The content of mtRNA normalizes in the aged heart after treatment secondary to increased RNA synthesis (32 , 33) . The increase in mtRNA synthesis leads to increased mitochondrial protein synthesis (chloramphenicol sensitive; ref 32 ), with increased content of mitochondrial-encoded electron transport subunits after acetylcarnitine treatment (32) . Based on the increases seen in the contents of cytochrome aa3 and b in the present study, it appears that stimulation of mitochondrial protein synthesis contributes to acetylcarnitine-mediated improvement in respiration in the aged heart.

In the current study, systemic administration of acetylcarnitine to the rat in vivo 3 h before ischemia protected the isolated heart subsequently exposed to in vitro ischemia and reperfusion. No additional drug was administered to the isolated heart. Direct in vitro administration of L-carnitine or propionyl-L-carnitine to isolated adult hearts reduced ischemic damage in some studies (34 35 36 37) , but not others (38 , 39) . Consistent with these variable results, acetylcarnitine administered in vitro directly to the isolated adult heart had a minimal protective effect (37) . In vivo acetylcarnitine treatment does not increase the activity of electron transport chain enzymes in the adult heart (15 , 20 , 40) , further supporting the selective aging-related effect on mitochondrial function observed in the current study. Acetylcarnitine decreased the production of ROS and blunted cellular injury in the aged liver during ischemia and reperfusion (41) .

Despite successful and sustained reperfusion of the infarct zone, the mortality of acute myocardial infarction in elderly patients remained elevated 6-fold compared to middle-aged patients (6) . Although pharmacologic treatment at the onset of reperfusion can reduce myocardial injury (42 , 43) , the option to use chronic pretreatment of high risk elders in a preemptive fashion before ischemia represents a novel cardioprotective strategy for the aged heart. The ability to modulate aging-induced defects in mitochondrial metabolism in order to reduce damage from ischemia and reperfusion is an attractive potential strategy to protect myocardium in the high-risk elderly patient suffering an acute myocardial infarction.

ACKNOWLEDGMENTS

These studies were supported grants 1RO1AG12447, 1RO1DK36069, 1K04AG00676, and 1PO1AG15885 from the National Institutes of Health.

Received for publication August 10, 2005. Accepted for publication March 14, 2006.

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