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,1
* Department of Chemistry,
¶ Department of Pharmacology and Toxicology, and
Department of Biochemistry, University of Otago, Dunedin, New Zealand; and
Medical Research Council Dunn Human Nutrition Unit, Cambridge, UK
1 Correspondence: MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 2XY, UK. E-mail: mpm{at}mrc-dunn.cam.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: TPP • oxidative damage • MitoQ
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2
3)
, the most effective of which is MitoQ (Fig. 1
A) (4)
. The lipophilic triphenylphosphonium cation (TPP) cation enables MitoQ to pass easily through phospholipid bilayers and leads to its selective, several hundred-fold concentration within mitochondria in living tissues dueto the large membrane potential (2
, 3
, 5)
(Fig. 1B
). Within mitochondria, MitoQ is reduced by the respiratory chain to its active ubiquinol form, which is a particularly effective antioxidant that prevents lipid peroxidation and mitochondrial damage (4)
(Fig. 1B
). In blocking oxidative damage, the ubiquinol is oxidized to a ubiquinone, which is reduced back to the active ubiquinol antioxidant by the respiratory chain (4)
. This selective accumulation and continual recycling by mitochondria make MitoQ several hundred-fold more potent at preventing mitochondrial oxidative damage than antioxidants, which are not accumulated (4
, 6
, 7)
. Therefore, these compounds offer a new therapeutic strategy for preventing mitochondrial oxidative damage, but whether they work in vivo is not yet known.
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To test the efficacy of mitochondria-targeted antioxidants within tissues in a clinically relevant form of mitochondrial oxidative damage, we chose a cardiac model of warm ischemia-reperfusion (IR) injury. During ischemia, the coronary blood supply to the heart is reduced or stopped preventing oxygen, glucose, and fatty acids from reaching the muscle (8)
. Ischemia inactivates oxidative phosphorylation, leading to a loss of adenine nucleotides and cytochrome c, a buildup of phosphate, fatty acids and lactic acid, increased cellular calcium, and a decrease in cellular pH, all of which disrupt mitochondria (8)
. Upon reperfusion, oxygen interacts with the damaged respiratory chain to produce a burst of reactive oxygen species (ROS) that underlies much IR injury (9)
. The proximal ROS produced is superoxide from respiratory complexes I and III (10)
. Superoxide damages the iron sulfur center in aconitase, releasing ferrous iron (11)
, and is dismutated to hydrogen peroxide, which reacts with ferrous iron to form the highly reactive hydroxyl radical (Fig. 1C
). The damaging oxidant peroxynitrite is also formed from the rapid reaction of superoxide with nitric oxide during IR (12)
(Fig. 1C
).
Hydroxyl radicals and peroxynitrite damage all mitochondrial components during IR injury, but phospholipids such as cardiolipin are particularly susceptible to oxidative damage, thereby disrupting respiratory complex I and increasing membrane permeability (13)
. The greater significance of mitochondrial relative to cytoplasmic oxidative damage during IR injury (14
, 15)
is well illustrated by the greatly increased susceptibility to IR damage in the SOD2(+/–) mouse heart, which has only 50% of the mitochondrial antioxidant enzyme MnSOD as SOD1(+/–) mouse hearts, which lack 50% of the cytosolic Cu,ZnSOD enzyme (14)
. Furthermore, increased MnSOD activity protects the heart against IR injury (16
, 17)
. Therefore, cardiac IR injury provides an attractive model for testing the effectiveness of mitochondria-targeted antioxidants in living tissues. Here we demonstrate that MitoQ decreased heart dysfunction, cell death, and mitochondrial damage after IR injury whereas an untargeted antioxidant was ineffective. Therefore, targeting antioxidants to mitochondria in vivo may be a promising new strategy to prevent mitochondrial oxidative damage in a wide range of human diseases where it contributes to the pathology.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Untargeted ubiquinone (Q3OH) was prepared by oxidation of 3-(2,3,4,5-tetramethoxy-6-methyl-phenyl)-propan-1-ol (18)
as follows: 3-(2,3,4,5-tetramethoxy-6-methyl-phenyl)-propan-1-ol (1.41 g, 5.5 mmol) was dissolved in a mixture of CH3CN and H2O (7:3, 25 mL) and stirred at 0°C in an ice bath. Pyridine-2,6-dicarboxylic acid (4.6 g, 27.3 mmol) was then added, followed by dropwise addition of a solution of ceric ammonium nitrate (15 g, 27.3 mmol) in CH3CN/H2O (1:1, 50 mL) over 15 min. The mixture was stirred at 0°C for 30 min, then at room temperature for a further 1 h. The reaction mixture was poured into H2O (100 mL), extracted with CH2Cl2 (100 mL), then dried (Na2SO4), filtered, and evaporated in vacuo to give crude Q3OH (1.14 g), which was chromatographed on a silica gel column. Elution with 30% diethyl ether/dichloromethane gave pure Q3OH (0.85 g, 67%) (19)
. 1H NMR (299.9 MHz) 
4.00, 3.99, (6H, s, OMe), 3.61 (2H, t, J=7.0 Hz, -CH2-OH), 2.58 (2H, t, Ar-CH2-), 1.69 (2H, quintet, J=7.0 Hz,-CH2-) ppm. Methyltriphenylphosphonium cation (TPMP) bromide, sucrose, Tris, EGTA, bovine serum albumin (BSA), glutamate, malate, succinate, rotenone, CoQ1, NADH, KCN, isocitrate, fluorocitrate, anti-ß-tubulin antibody, and the LDH (LD-L) kit were obtained from Sigma-Aldrich (St. Louis, MO, USA). Paraformaldehyde and glutaraldehyde were obtained from BDH (Dorset, UK). Anti-caspase 3 antibody was purchased from Transduction Laboratories (Lexington, KY, USA). Immunoblotting materials and molecular weight markers were supplied by Bio-Rad (Hercules, CA, USA). Quantikine Rat/Mouse cytochrome c ELISA kit was from R&D Systems (Abingdon, Oxon, UK). Uranyl acetate, lead citrate and Agar 100 resin were from Agar Scientific Ltd. (Stansted, Essex, UK). Osmium tetroxide was from ProSciTech (Queensland, Australia).
Animals and compound administration
Male Wistar rats (140–160 g, 45–55 days old at the beginning of the treatment and 280–320 g at the end of the treatment) were allowed free access to tap water or tap water containing 500 µM MitoQ, Q3OH, or TPMP for 14 days. The MitoQ, Q3OH, and TPMP solutions were prepared fresh every 3 days, protected from the light, and stored at 4°C. The stability of the MitoQ solutions was confirmed by spectroscopic analysis and solutions were considered to be stable if A275 = 0.73 ± 0.1. The amount of the solution of each compound drunk was 174 ± 6 mL·kg–1 day–1 (=42±2 mL·day–1rat–1); for water the value was 197 ± 7 mL·kg–1day–1 (48±1 mL·day–1rat–1). This consumption corresponds to 74–99 µmol compound·kg–1day–1. Despite slight differences in the amounts drunk, weight gain (7.8±0.3 g·day–1) was the same for controls and for the MitoQ-, TPMP-, or Q3OH-fed rats. No behavioral changes or gross pathology were observed in the rats over this time, consistent with earlier studies (3
, 20)
. All experiments were carried out in accordance with the guidelines (1987) on The Care and Use of Laboratory Animals by the University of Otago Animal Ethics Committee.
Isolated heart perfusion protocol and hemodynamic assessment
Rats were anesthetized with diethyl ether and systemically heparinized (500 USP units, IV). The hearts were rapidly excised and placed into 4°C Krebs-Henseleit (KH) buffer [118 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO4, 1.23 mM KH2PO4, 24 mM NaHCO3, 11.1 mM glucose, 1.2 mM CaCl2 (pH 7.4)]. Within 30 s of excision, hearts were cannulated through the aorta and retrogradely perfused with oxygenated (95% O2/5% CO2) KH buffer at a constant pressure of 100 cm H2O at 37°C, using a Langendorff rig as described previously (21)
. The base of the pulmonary artery was cut to assist drainage. After 20 min of equilibration to Langendorff perfusion, ventricular contractile function was assessed using a balloon inserted into the left ventricle. Briefly, the balloon was attached to a physiological pressure transducer in order to assess left ventricular function at an end diastolic pressure of 10 mm Hg. Cardiac function was characterized by left ventricular developed pressure (LVDP) derived from the difference between peak systolic pressure and diastolic pressure. Coronary effluent flow was measured at 10 mm Hg. Ventricular pressure, dP/dt max, and heart rate (HR) were measured using Chart v4.2 (AD Instruments, Castle Hill, Australia). After 30 min of normoxic perfusion, the heart was subjected to 30 min warm (37°C) global zero flow ischemia. The heart was then normoxically reperfused for 60 min and hemodynamic parameters reassessed at 0, 20, 40, and 60 min postischemia.
Effluent buffer samples were collected at pre- (20 min) and post- (60 min) ischemic time points and assessed for lactate dehydrogenase (LDH) activity (22)
. Briefly, 40 µL of effluent sample was added to 250 µL reaction mixture containing 0.139 mM NADH and 4.63 mM pyruvate in 38.6 mM phosphate buffer (pH 7.5) in a microtiter plate and mixed. LDH activity based on the conversion of NADH to NAD+ was assayed at 340 nm at 25°C for 3 min and calculated as the difference between the natural logarithms of A340 at 25°C for three time points: 1, 2, and 3 min after addition of tissue homogenate protein. Results are expressed as µmol NAD reduced per min (23)
. Protein concentration was assayed using a microplate variation of the Lowry assay using BSA as a standard (24)
.
Tissue fixation and transmission electron microscopy
Hearts were perfusion-fixed via the aorta with 2% paraformaldehyde/2.5% glutaraldehyde in KH buffer for 5 min either prior to ischemia or after 60 min reperfusion. Left ventricular tissue was dissected out and sections (
3 mm3) were further fixed for 2 h in 2% paraformaldehyde/2.5% glutaraldehyde. Tissue samples were postfixed in 1% osmium tetroxide en bloc, stained with 1% uranyl acetate in 0.05 M sodium hydrogen maleate buffer, dehydrated through an ethanol series, and embedded in Agar 100 resin. Ultra-thin sections were stained with 1% uranyl acetate and lead citrate and examined using a Philips CEM100 transmission electron microscope (21)
.
Tissue homogenization and mitochondrial preparations
Immediately after the pre- and postischemic periods, ventricular tissue from each perfused heart was removed by cutting across the upper limit of the ventricles. To assess cytochrome c release and caspase activation, ventricular tissue was homogenized in ice-cold mitochondrial isolation buffer [225 mM mannitol, 75 mM sucrose, 10 mM Tris base, 2 mM EGTA (pH 7.2)] together with Complete, Mini, EDTA-free protease inhibitor cocktail (Roche, Nutley, NJ, USA); the supernatant was prepared by sequential centrifugation at 11,500 g, then at 100,000 g. The cytosol was diluted 1:20, then assessed for cytochrome c content using an Quantikine Rat/Mouse cytochrome c ELISA kit from R&D Systems according to the manufacturer’s instructions. Caspase activation was assessed by separating out cytosolic extract using SDS-PAGE (15% gel) and transferring proteins to a nitrocellulose membrane. Cleaved caspase 3 p17 fragments were detected using a mouse monoclonal anti-caspase 3 antibody (Transduction Laboratories) raised against amino acids 25-145. Antibody binding was detected by a horseradish peroxidase goat anti-mouse antibody using Super Signal West Dura substrate (Pierce Biotechnologies, Rockford, IL, USA). ß-Tubulin levels were quantified from the same blots using a mouse monoclonal anti-ß-tubulin antibody (Sigma) to ensure equal sample loading. Caspase 3 p17 bands were quantified on hyperfilm using a Bio-Rad GS-710 scanning densitometer and analyzed using Quantity One software.
To prepare mitochondria (21)
, ventricular tissue from each animal was minced for 8 min in ice-cold mitochondrial isolation buffer containing 0.1 mM phenylmethylsulfonyl fluoride and Nagarse protease (0.625 mg/mL; Sigma) to ensure recovery of interfibrillar and sarcolemmal mitochondrial populations. The tissue was then washed five times to remove the Nagarse and homogenized in two separate aliquots, using a Potter-Elvehjem homogenizer. The homogenate was centrifuged at 3500 g for 3.5 min at 4°C and the supernatant centrifuged at 11,500 g for 12 min at 4°C to pellet mitochondria. The pooled mitochondrial fractions were washed in fresh mitochondrial isolation buffer and recentrifuged at 11,500 g for 12 min at 4°C to produce a final pellet containing both sarcolemmal and interfibrillar mitochondria. Mitochondria were resuspended in 500 µL mitochondrial isolation buffer and the protein concentration was measured by the Lowry method using BSA as a standard (24)
.
Respiration measurements
Mitochondrial oxygen consumption was measured using a water-jacketed Clark-type oxygen electrode at 30°C (World Precision Instruments, Sarasota, FL., USA) and recorded using Chart v3.5 (AD Instruments). Incubations were performed by adding 0.5 mg mitochondrial protein from each sample and 0.125 mg fat-free BSA to 200 µL mitochondrial respiration medium [100 mM KCl, 75 mM mannitol, 25 mM sucrose, 10 mM Tris, 10 mM KH2PO4-Tris, 0.1 mM K–EDTA, (pH 7.4)] as described previously (21)
. State 4 respiration was initiated using 7 mM each of glutamate and malate or 7 mM succinate in the presence of 50 µM rotenone. State 3 respiration was initiated by the addition of 200 µmol ADP.
Mitochondrial enzyme assays
Mitochondrial samples were snap frozen and stored at –80°C. Prior to assay they were disrupted by three cycles of freeze-thawing, then stored on ice. Complex I was assayed from the CoQ1-dependent and rotenone-sensitive oxidation of NADH (25)
. To each well of a 96-well microtiter plate was added 250 µL phosphate buffer [8 mM MgCl2, 40 mM KPi (pH 7.2)] supplemented with 2.4 mg.mL–1 BSA, 160 µM NADH, and 2.4 mM KCN (23)
. Mitochondrial sample (10 µg protein) was added to the plate in triplicate. After 2 min, 200 µM CoQ1 was added to each well. The plate was mixed and assayed at 340 nm at 30°C on a SpectraMaxPlus spectrophotometer (Molecular Devices, Sunnyvale, CA, USA) for 5 min. The enzyme inhibited rate was assessed in the presence of 0.5 µM rotenone and read for a further 5 min. Aconitase was assayed as the fluorocitrate-inhibitable increase in aconitate at 240 nm (26)
. Mitochondrial protein (8 µg) was added to 240 µL of 100 mM Tris base (pH 8) in a 96-well microtiter plate, after which 25 µL isocitrate (200 mM) was added to each well. The plate was mixed and assayed at 240 nm at 30°C on a SpectraMaxPlus spectrophotometer for 5 min; 8 µL of fluorocitrate (11 mM) was added to each well, the plate was assayed for a further 10 min, and samples were run in triplicate. Complexes II, III, and IV were assayed as described (27)
.
MitoQ tissue loading analysis
Tissue analysis was carried out by overnight enzymatic digestion of the whole heart with protease (Savinase, Novo Nordisk A/S, Denmark), followed by extraction of the digest with acetonitrile and evaporation. The extract was reconstituted for LC/MS/MS analysis on a Sciex API 2000 mass spectrometer using the 583-441 transition. The internal standard was MitoQ-d3 using the 586-444 transition.
Statistical analysis
Statistical analysis was performed using SigmaStat v2.03. Statistical significance was determined by a 1-way ANOVA and a Bonferroni post hoc test to compare pre- and postischemic controls and the effects of compounds. All values are expressed as the mean ± SE. A P value of <0.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The hearts were then removed and perfused using a Langendorff constant pressure system (21)
. Cardiac function was assessed by measuring left ventricular developed pressure (LVDP; Fig. 2
A), the maximum rate of change in left ventricular pressure (dP/dt; Fig. 2B
), coronary flow (Fig. 2C
), and heart rate (Fig. 2D
). Hearts were exposed to 30 min warm (37°C) global ischemia by stopping cardiac perfusion, followed by a 60 min reperfusion period during which recovery of cardiac function was monitored (Fig. 2A-D
). IR injury resulted in a dramatic loss of cardiac function that was significantly ameliorated by MitoQ (Fig. 2A-D
). The short chain ubiquinol Q3OH (Fig. 1A
), which has the same antioxidant moiety as MitoQ but is not taken up by mitochondria, was ineffective against three of the markers of cardiac dysfunction (Fig. 2A, B, D
), although it did provide slight protection of coronary flow values (Fig. 2C
). Methyltriphenylphosphonium (TPMP; Fig. 1A
), the targeting cation component of MitoQ, did not protect against IR injury. Therefore, protection of heart function was due to the antioxidant efficacy of MitoQ within mitochondria and was not a consequence of the mitochondrial accumulation of a lipophilic cation.
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MitoQ protects against tissue damage during IR injury
To see whether MitoQ protected heart function by preventing tissue damage, we measured leakage of the cytosolic enzyme lactate dehydrogenase (LDH) into the perfusate as an indication of cardiomyocyte damage (Fig. 3
A). There was minimal LDH release prior to ischemia (Fig. 3A
), but after IR injury there was a dramatic increase in LDH release by control hearts, indicating extensive cell death (Fig. 3A
, postischemic control). LDH release was significantly decreased by MitoQ (Fig. 3A
). To confirm that MitoQ prevented tissue damage during IR injury, we assessed cardiac ultrastructural morphology by transmission electron microscopy (Fig. 3B
). Heart tissue fixed before ischemia showed normal myocardial structure with regular myofibrils interspersed with intact mitochondria and T tubules (Fig. 3B, i
). In contrast, tissue fixed 60 min after reperfusion had extensive tissue damage indicated by disordered myofibrils, structural disruption to myotubules, and mitochondrial swelling (Fig. 3B, ii
). MitoQ did not affect tissue ultrastructure prior to IR (Fig. 3B, iii
), but largely prevented the tissue damage and mitochondrial swelling caused by IR injury (Fig. 3B, iv
). IR injury induces phospholipid peroxidation leading to mitochondrial swelling and release into the cytosol of proapoptotic proteins such as cytochrome c (28
, 29)
. Cytochrome c was released from the mitochondria into the cytosol during IR and this release was decreased by MitoQ (Fig. 3C
). The caspase-dependent apoptotic pathway was initiated by cytochrome c release during IR injury, as indicated by caspase 3 activation (Fig. 3D
); this was significantly blocked by MitoQ (Fig. 3D
). Therefore, cardiac IR injury leads to extensive tissue damage and cell death associated with mitochondrial swelling, cytochrome c release, and caspase activation, all of which are significantly decreased by MitoQ.
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MitoQ protects against disruption to mitochondrial function during IR injury
To see whether protection against cardiac dysfunction and cell death during IR was a consequence of protecting mitochondria, we isolated mitochondria from the perfused hearts before and after IR injury and measured their respiratory function (Fig. 4
A, B). The respiratory control ratio (RCR) is the ratio of state 3 to state 4 respiration rates. A high state 3 rate indicates an intact respiratory chain and ATP synthesis; a low state 4 rate indicates an intact mitochondrial inner membrane (30)
. Therefore, the high RCRs of mitochondria from preischemic hearts indicate intact, active mitochondria (Fig. 4A, B
). In contrast, mitochondria isolated after IR injury had dramatically decreased RCRs, diagnostic of extensive mitochondrial damage (Fig. 4A, B
). MitoQ significantly prevented this decrease in RCR whereas TPMP or Q3OH were ineffective (Fig. 4A, B
). The protective effect of MitoQ on the glutamate and malate RCR was largely due to maintenance of state 3 respiration (Fig. 4C
); the effect on succinate state 3 respiration was less (data not shown). Glutamate and malate donate electrons to the respiratory chain through complex I via NADH whereas succinate passes electrons directly to complex II, suggesting that complex I was specifically damaged during IR injury (31)
. This was confirmed by measuring the specific activity of complex I; MitoQ significantly prevented this complex I damage (Fig. 4D
). The decreased succinate-driven RCR after IR injury was largely due to increased state 4 respiration from elevated proton leak through the mitochondrial inner membrane; this was also blocked by MitoQ (Fig. 4E
). The activity of the superoxide-sensitive mitochondrial enzyme aconitase decreased upon IR injury (Fig. 4F
). However, this decrease in activity was not prevented by MitoQ, indicating that the antioxidant action of MitoQ occurs downstream of superoxide.
|
Mitochondrial oxidative damage during IR is a consequence of increased superoxide production leading to iron release from aconitase in conjunction with the formation of hydrogen peroxide and peroxynitrite (Fig. 1C
). Together, these pro-oxidants initiate phospholipid peroxidation and subsequent damage to complex I, increased membrane leak, mitochondrial swelling, cytochrome c release, caspase activation, and cell death (31)
. The amount of MitoQ present in hearts in our experiments was 20 ± 9 pmol MitoQ/g wet weight ventricular tissue. From the mitochondrial water con-tent of the rat heart [153 µL/g wet weight (32)
], this corresponds to an intramitochondrial MitoQ concen-tration of 100–200 nM, similar to that which protects mitochondria in cells from iron-initiated oxidative damage in vitro (6)
. Therefore, our findings suggest that MitoQ blocks this destructive cascade by preventing mitochondrial phospholipid peroxidation and complex I damage during IR (Fig. 1B
).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this report, protection against cardiac IR was used primarily as a proof of principle. However, MitoQ may be of value as a therapeutic adjunct to clinical procedures associated with cardiac IR injury such as coronary artery angioplasty and bypass grafting and in open heart surgery and transplantation (15
, 33)
, particularly for patients such as the elderly with poor prognosis due to diminished antioxidant protection (34)
. More generally, our finding that mitochondria-targeted antioxidants are effective after oral delivery is an important step toward developing protective therapeutic strategies for the wide range of diseases with mitochondrial oxidative damage in their etiology (35
, 36)
. Unlike many conventional antioxidants, these compounds cross the blood-brain barrier (3)
, and so may be particularly useful for neurodegenerative diseases to which mitochondrial oxidative damage contributes, such as Parkinson’s disease, Friedreich’s ataxia, and Huntington’s disease (2
, 35)
. As delivery to mitochondria by conjugation to a TPP cation can be applied to many other antioxidants and pharmacophores, this strategy could be extended to improve antioxidant efficacy, delivery, and bioavailability (2
, 3)
.
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ACKNOWLEDGMENTS |
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Received for publication January 23, 2005. Accepted for publication February 24, 2005.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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p), then further accumulates within mitochondria driven by mitochondrial membrane potential (
