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Previous Article | Next Article 
Molecular and Cellular Biology, December 2005, p. 10261-10272, Vol. 25, No. 23
0270-7306/05/$08.00+0 doi:10.1128/MCB.25.23.10261-10272.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 7, 1030 Vienna, Austria,1 Departments of Immunology,2 Medical Biophysics, University of Toronto, Toronto, Ontario, Canada,3 Departments of Physiology and Medicine, Division of Cardiology, University Health Network, and Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario, Canada,4 Department of Anatomy, University of California at San Francisco, San Francisco, California 94143-2711,5 INSERM U676, Hopital Robert Debre, 75019 Paris, France,6 Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, Villejuif, France,7 Max F. Perutz Laboratories, Departments of Microbiology and Genetics, University of Vienna, Campus Vienna Biocenter, A-1030 Vienna, Austria8
Received 16 August 2005/ Accepted 17 August 2005
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ABSTRACT |
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INTRODUCTION |
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In addition to functioning as the powerhouses of the cell, mitochondria are essential to a cell's suicide machinery, initiating apoptosis through the release of potentially toxic proteins from the mitochondrial intermembrane space into the cytosol (7, 14). One of these mitochondrial proteins is the hemoprotein cytochrome c, whose role in healthy cells is to shuttle electrons from complex III to IV of the respiratory chain. However, during apoptosis, cytosolic cytochrome c stimulates formation of the apoptosome, a caspase-activating complex (4). In addition to cytochrome c, other apoptotic effectors are released from mitochondria, including the serine protease Omi/Htra2, Smac/Diablo, endonuclease G, and apoptosis-inducing factor (AIF) (7).
AIF is an evolutionarily conserved flavoprotein closely associated with the inner mitochondrial membrane (36). In several cellular contexts in species including yeast, Caenorhabditis elegans, and in mammals, AIF has been implicated as a cell death-promoting molecule that translocates from mitochondria to the nucleus after proapoptotic signals and mediates chromatin condensation and large-scale DNA fragmentation (18, 25, 36, 42, 43). In addition to its cell death effector functions, AIF has been shown to be required for cell survival and has been suggested to function as a scavenger of reactive oxygen species (ROS) (19). The Harlequin (Hq) mouse mutant, which manifests an 
80% reduction in AIF protein levels due to a proviral insertion in the first intron of the Aif gene, exhibits progressive cerebellar and retinal degeneration associated with increased levels of oxidative stress markers (20). Recently, it has been shown that cardiomyocytes from Hq mice were sensitized to oxidative stress-induced cell death, and Hq hearts displayed more severe ischemic damage compared to wild-type hearts after acute ischemia/reperfusion injury (38). In addition, we have reported a requirement for AIF in OXPHOS and for the assembly and/or stabilization of respiratory complex I (37). It remains unclear, however, whether AIF functions primarily in scavenging cellular ROS or controlling OXPHOS function. Moreover, the in vivo consequences of a targeted Aif null mutation on mouse embryonic development and in adult tissues have not been explored.
Here we report the targeted disruption of Aif in mice. Loss of AIF expression during embryogenesis results in embryonic growth retardation and death during midgestation. Mice lacking AIF in muscle develop severe dilated cardiomyopathy and skeletal muscle atrophy, associated with a severe defect in respiratory chain complex I activity, significantly reduced levels of complex I proteins, and metabolic alterations that resemble human mitochondriopathies. We demonstrate that AIF-regulated mitochondrial respiration and energy homeostasis are critical for normal heart function and skeletal muscle maintenance.
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MATERIALS AND METHODS |
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10-kb fragment spanning exons 8 to 14, and a 600-bp fragment 5' of exon 7, cloned into a targeting vector backbone containing PGKneo and DTA-positive and -negative selection cassettes, respectively. The linearized construct was electroporated into E14Tg2a.4 embryonic stem (ES) cells, derived from the 129/Ola strain (16). Approximately 1 in 100 ES cell clones were identified as correctly targeted by genomic Southern blotting. Five such clones were transiently transfected with the pCAGGs-FLPe vector (3) to excise the frt-flanked PGKneo cassette. Subclones that no longer contained the PGKneo cassette as determined by Southern blot were injected into C57BL/6 blastocysts. Chimeric mice from two independent clones transmitted the mutant allele through the germ line. Mice carrying the Aifflox allele were backcrossed two to four times to C57BL/6 mice before generating the Mck-cre; Aifflox/Y animals. It should be noted that we observed similar phenotypes in Mck-cre; Aifflox/Y males and Mck-cre; Aifflox/flox females. For mouse genotyping, genomic DNA from mouse tails was isolated and amplified by PCR with three primers: P1, 5'-GAATCTGGAATATGGCACAGAGG-3'; P2, 5'-GGATTAAAGGCATGTGCCAACACG-3'; and P3, 5'-GTAGATCAGGTTGGCCAGAAACTC-3'. PCR products were ca. 700 bp (floxed allele, P2 + P3), 600 bp (wild-type allele, P2 + P3), and 400 bp (
ex7 allele, P1 + P3), respectively. The Mck-cre transgene was detected by using the forward primer 5'-TCGCGATTATCTTCTATATCTTCAG-3' and reverse primer 5'-GCTCGACCAGTTTAGTTACCC-3'. Mice were bred and maintained according to institutional guidelines. Analyses of mRNA, protein expression, and metabolite concentrations. Western blotting was carried out as described previously (6) with antibodies to the C-terminal portion of AIF (AB16501; Chemicon); actin (A-2066; Sigma); cytochrome c (Pharmingen); and respiratory chain complex I subunits 39kDa, 30kDa, and 20kDa (all Molecular Probes). For TaqMan real-time PCR analysis of atrial natriuretic factor (ANF) and B-type natriuretic peptide (BNP) expression, 1 µg of DNase-treated total RNA extracted from hearts was reverse transcribed by using oligo(dT). TaqMan reactions were carried out in 96-well plates with 0.5% cDNA, 12.5 µl of 2x TaqMan universal PCR Mastermix, 100 µM probe, 200 µM concentrations of each primer, and water to a final volume of 25 µl. 18S rRNA was used as a control. Blue-native polyacrylamide gel electrophoresis (BN-PAGE) was carried out as described previously (33). Briefly, mitochondria isolated from heart and gastrocnemius were solubilized with extraction buffer containing 1% n-dodecyl-maltoside and centrifuged at 100,000 x g for 30 min, and the supernatant was analyzed on a 5 to 18% polyacrylamide gradient gel, followed by staining with Coomassie blue. For analysis of plasma metabolite levels, mice were anesthetized with ketamine-xylazine; blood was drawn by cardiac puncture and immediately deproteinated in 1 M perchloric acid. Levels of organic acids, electrolytes, and glucose were determined by conventional methods at the Hôpital Necker-Enfants Malades, Paris, France.
Histological and morphometric analyses. For heart histology, hearts were arrested with 1 M KCl, fixed with 10% buffered formalin, and subsequently embedded in paraffin. Skeletal muscles were snap-frozen in liquid N2-cooled isopentane, and hematoxylin and eosin and succinic dehydrogenase (SDH) activity stains (26) were performed on cryostat sections. Myocyte areas were quantified by using Oracle imaging software. Samples for electron microscopy were prepared essentially as described previously (18).
Echocardiography and invasive hemodynamic measurements. Echocardiographic and hemodynamic measurements were performed as described previously (6). Briefly, mice were anesthetized with isoflurane(1%)/oxygen, and echocardiographed using an Acuson Sequoia C256 equipped with a 15-MHz linear transducer. Fractional shortening (FS) was calculated as follows: FS = [(EDD – ESD)/EDD] x 100. Vcfc was calculated as FS/ejection time corrected for heart rate. For hemodynamic assessments, the right carotid artery was cannulated with a 1.4 French Millar catheter (Millar, Inc., Houston, TX) connected to an amplifier (TCP-500; Millar, Inc.) After insertion of the catheter into the carotid artery, the catheter was advanced into the aorta and then into the left ventricle to record the aortic and ventricular pressures.
Langendorff perfusion experiments. Mck-cre; Aifflox/Y mutant and littermate control mice were anesthetized with ketamine-xylazine, and isolated hearts were immediately placed in cold phosphate-buffered saline. Hearts were then perfused in the retrograde Langendorff mode with modified glucose-free, pyruvate-containing Kreb's solution (116 mM NaCl, 3.2 mM KCl, 1.2 mM MgSO4, 25 mM NaHCO3, 1.2 mM KH2PO4, 2 mM CaCl, 0.5 mM EDTA, 3 mM sodium pyruvate) in the presence of 95% O2 and 5% CO2 to achieve a final pH of 7.4. A pressure transducer balloon was inserted into the left ventricle, and the consequent pressure waveform was recorded at 2 kHz using a Biopac acquisition system. Baseline data was acquired over a 4-min interval. After this period the solution was switched to a pyruvate-free glucose-based Kreb's solution (116 mM NaCl, 3.2 mM KCl, 1.2 mM MgSO4, 25 mM NaHCO3, 1.2 mM KH2PO4, 2 mM CaCl, 0.5 mM EDTA, 10 mM glucose), and continuous recordings were obtained for a further 10 min. The temperature was maintained at 36 ± 0.5°C during all recordings.
Assays of mitochondrial function. Mitochondria were prepared by homogenizing heart, skeletal muscle, or liver from Mck-cre; Aifflox/Y mutant and littermate control mice in homogenization medium (250 mM sucrose, 5 mM Tris-HCl, 2 mM EGTA [pH 7.2]) at 4°C. The homogenate was centrifuged at 760 x g for 10 min at 4°C to remove nuclei and cellular debris. The supernatant was then centrifuged at 8,740 x g. The pellet was resuspended in homogenization medium, layered onto a 60%-30%-18% sucrose Percoll gradient, and centrifuged at 8,460 x g. Purified mitochondria were washed two times in homogenization buffer. All steps were carried out at 4°C. Rotenone-sensitive NADH quinone reductase (CI; EC 1.6.5.3), malonate-sensitive succinate quinone dichlorophenol indophenol (DCPIP) reductase (CII; EC 1.3.99.1), antimycin-sensitive quinol cytochrome c reductase (CIII; EC 1.10.2.2), cyanide-sensitive cytochrome c oxidase (CIV; EC1.9.3.1), and oligomycin-sensitive ATP hydrolase (CV; EC 3.6.3.14) were spectrophotometrically measured by using a dual-wavelength spectrophotometer (SLM-Aminco DW-2A; SLM Instruments, Inc., Urbana, IL) as described previously (1, 32). All measurements were performed at 37°C. Protein levels were determined by the method of Bradford with bovine serum albumin as a standard. All chemicals were analytical reagent grade from Sigma Chemical Company.
Lipid peroxidation, catalase activity, and glutathione assays. Lipid peroxidation was analyzed as described previously (30). Catalase activity and total glutathione levels were quantified by using the catalase assay and glutathione assay kits according to the manufacturer's instructions (Cayman Chemicals). Proteins were quantified by using a BCA kit (Pierce).
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RESULTS |
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ex7, a presumed null allele, early in embryogenesis. Female progeny of this cross that are heterozygous for the Aifflox allele (ß-actin-cre; Aifflox/+) are born at lower frequencies than expected for Mendelian inheritance, indicating that some female mutant heterozygotes die in utero. Those that survive to birth are smaller in size than their wild-type littermates but otherwise appear healthy and fertile. In contrast, ß-actin-cre; Aifflox/Y mutant embryos are present at the expected Mendelian frequency between embryonic day 7.5 (E7.5) and E10.5 but exhibit severe growth retardation (Fig. 1B). No viable embryos could be recovered after E12.5 (a detailed analysis of the AIF null phenotype will be described elsewhere.) Thus, complete loss of Aif in the early embryo results in a growth arrest and death by E12.5.
Progressive skeletal muscle atrophy in AIF muscle mutant mice.
To study the role of AIF in adult tissues that have high energy requirements, we conditionally inactivated Aif in cardiac and skeletal muscle by crossing mice carrying Aifflox with a transgenic line expressing cre under the control of the muscle creatine kinase promoter (Mck-cre). It has been shown previously that this transgene efficiently excises loxP-flanked sequences in the heart as well as in all skeletal muscles tested, regardless of anatomical localization or muscle fiber type (2). Crosses of Aifflox/+ mice with Mck-cre homozygotes produced viable Mck-cre; Aifflox/Y progeny at the expected Mendelian frequency (25%). PCR analysis and Western blotting confirmed that Aif exon 7 was excised (Fig. 1C and D) and that AIF protein expression was abolished (Fig. 1D) specifically in heart and skeletal muscle tissue from Mck-cre; Aifflox/Y mutants. As expected, the Aif gene did not undergo recombination in other tissues tested (Fig. 1C and D).
Whereas Mck-cre; Aifflox/Y mutant animals appeared normal at 2 months of age, after 3 months a striking loss in muscle mass and body weight was observed in mutants compared to littermate control mice (Fig. 2A). (Littermate controls used throughout the present study were Mck-cre; Aif+/Y and Aifflox/Y mice; no phenotypic differences were observed between these genotypes.) All skeletal muscles analyzed, including triceps, pectoralis, quadriceps, gluteus, and gastrocnemius muscles were significantly atrophied in mutant mice (Fig. 2B). The loss in body weight (Fig. 2C) and degeneration in musculature (Fig. 2D) were progressive, becoming readily detectable after 10 weeks of age. Interestingly, these skeletal muscle changes were more pronounced in predominantly fast-twitch muscles (gastrocnemius, triceps, and quadriceps) compared to the slow-twitch soleus muscle. Atrophy of the skeletal musculature in Mck-cre; Aifflox/Y mutant mice was accompanied by structural changes. Myofiber cross-sectional area was reduced by >2-fold in triceps of 3-month-old mutant mice compared to those from littermate controls (Fig. 2E, F, and I). Moreover, myofibers in skeletal tissue from 3-month-old mutant mice displayed irregular contours (Fig. 2E and F). Histochemical analysis of muscle tissue sections for SDH activity, an indicator of mitochondrial numbers (13), revealed no obvious abnormalities (Fig. 2G and H). The progressive loss in muscle mass in mutants left the mutant animals increasingly lethargic and, by 5 months of age, they were sacrificed for ethical reasons. Thus, genetic ablation of Aif expression in skeletal muscle results in progressively severe deterioration of the skeletal musculature and muscle atrophy.
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2.5-fold increase in plasma lactate levels compared to their littermate controls (Table 2). This increase in blood lactate levels was progressive and correlated with the loss in muscle mass (not shown). In mutant mice, a concomitant and significant increase in the lactate/pyruvate ratio was observed. Other blood chemistry parameters analyzed such as glucose and electrolytes such as Ca2+ appeared normal in Mck-cre; Aifflox/Y mice. Elevated blood lactate/pyruvate ratios are commonly observed in patients and mouse mutants with mitochondrial myopathies (13, 28, 41).
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AIF has been previously reported to function as a scavenger of ROS based in part on the observation that neuronal tissue from mice carrying a hypomorphic mutation in Aif exhibit high levels of lipid and DNA markers of oxidative stress (20). We quantified the activity of the antioxidant catalase, the principal scavenger of hydrogen peroxide in the cell (8). At 5 weeks of age, hearts and skeletal muscle from mutant and control animals did not exhibit significant differences in levels of catalase activity (Fig. 6A). However, at 4.5 months of age, profound increases in catalase activity were observed in mutant animals compared to controls. Levels of glutathione, an essential electron donor for the reduction of hydroperoxides, were similar between wild-type and mutant hearts (Fig. 6B). Finally, we quantified the levels of lipid peroxidation products malondialdehyde, hexanal, and 4-hydroxynonenal (11). We found that these markers were elevated >2.5-fold in the hearts of 9-week-old Mck-cre; Aifflox/Y mutant mice compared to control littermates (Fig. 6C). Thus, loss of AIF results in increased levels of some markers of oxidative stress and impaired mitochondrial respiration.
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DISCUSSION |
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80% reduction in AIF protein levels and exhibit late-onset ataxia and degeneration of retinal and cerebellar neurons (20, 37). In the present study, we extend these findings into mice carrying a null allele of the Aif gene. We show that loss of AIF during embryogenesis results in growth arrest and death by E12.5. It seems likely that the phenotype results from defects in mitochondrial respiration, since we show that inactivation of AIF in heart and skeletal muscle leads to compromised complex I function in these tissues. Moreover, mutation of genes encoding components of the respiratory chain or regulating mitochondrial respiration leads to early embryonic growth retardation and lethality (22, 24). We demonstrate further that AIF is required for the maintenance of normal heart and skeletal muscle function. Inactivation of AIF in these tissues results in dilated cardiomyopathy, progressive muscle atrophy and weakness, and lactic acidemia. This physiological and metabolic profile resembles characteristics of mitochondrial myopathies and cardiomyopathies from patients with defects in OXPHOS (39, 40). Such alterations are also observed in genetically altered mutant mice with primary OXPHOS defects (13, 21, 41). For example, mice carrying a mutation in the gene encoding the muscle isoform of adenine nucleotide translocator (ANT1) develop cardiac hypertrophy with mitochondrial proliferation, elevated serum lactate levels, and muscle fatigue after exercise (13). It is noteworthy that we did not observe in our mutant mice ragged-red muscle fibers (Fig. 2G and H), which are indicative of mitochondrial proliferation and are observed in some other mouse models of mitochondrial myopathies (13, 44). This discrepancy may relate to the fact that the respiratory defect in our mutants is more limited, affecting predominantly complex I, than in these other mutant mouse models. Our data point to a role for AIF in mitochondrial respiration and energy metabolism essential for normal tissue function.
It has been suggested previously that AIF controls the cellular redox state by functioning as a scavenger of free radicals (19, 20). In support of this, cerebellar and retinal neurons from the Harlequin (Hq) mouse exhibit increased oxidative stress and cerebellar granule cells display increased sensitivity to hydrogen peroxide-mediated cell death in culture (20). Recently, it has been shown that hearts from Hq mice exhibit more severe tissue damage after acute ischemia-reperfusion injury and Hq cardiomyocytes are sensitized to oxidative stress-induced cell death (38). In line with these findings, our muscle-specific AIF mutants displayed elevated levels of oxidative stress, including increased catalase activity and lipid peroxidation. Since defects in respiratory chain function can result in increased oxidative stress (10) and in light of our data demonstrating defects in complex I function in Aif mutant mice, we suggest an alternative interpretation of the Hq phenotype, namely, that the primary defect resulting from loss of AIF expression is impaired mitochondrial respiration, which then leads to the observed upregulation of oxidative stress markers. Moreover, if impaired OXPHOS were secondary to increased oxidative stress, then one might expect to see more generalized defects in complexes I, II, and III, as are observed in genetically altered mice carrying mutations in antioxidant defense genes, such as the SOD2 and frataxin knockout mice (27, 31). However, such generalized defects were not observed in our mutant animals. Although we cannot exclude a role for AIF as an antioxidant, we favor the notion of a primary role for AIF in regulating mitochondrial respiration. Indeed, neuronal degeneration is frequently observed in patients and animal models with defective OXPHOS (21).
In addition to a complex I functional defect in our AIF mutant animals, we observed milder defects in complex IV activity, particularly in the heart. This may result from destabilization of the postulated I/III/IV supercomplex subsequent to defects in complex I (34). The mechanism by which AIF regulates mitochondrial respiration through complex I (and possibly other respiratory complexes) remains to be determined. AIF does not interact with complex I nor does loss of AIF affect transcription of complex I subunits (37). Since AIF-deficient tissues exhibit a reduced content of complex I and its components, AIF may play a role in the biogenesis and/or stability of the complex. Very little is known of the mechanism of complex I assembly, and only one assembly factor has been identified in mammals (35). The redox activity of AIF might play a role in controlling the redox status of one key component of complex I, either necessary for the correct assembly/maintenance of the complex or for normal electron transfer through the complex.
AIF was originally characterized as a caspase-independent apoptogenic molecule and has since been shown to participate and, in some cases, to be required in multiple systems of cell death. For instance, knockdown of Aif expression in Caenorhabditis elegans using RNA interference prolonged duration of development as a result of inefficient programmed cell death (42). Cortical neurons from Hq mice as well as Aif-null murine ES cells exhibited partial resistance to cell death after serum withdrawal (18, 20). This apparent functional duality of AIF underscores the notion that the apparatus involved in the suicide of a cell is intimately linked to basic cellular life-sustaining processes.
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ACKNOWLEDGMENTS |
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This study was supported by grants from IMBA, the Austrian National Bank Jubilaeumsfonds, and the Austrian Academy of Sciences (to J.M.P.); grants from LNC, EU, and Ministere pour la Recherche (to G.K.); and an Ontario Graduate Scholarship (to N.J.) and an ARC fellowship (N.V.). P.H.B. and P.R. thank the Association Française contre les Myopathies and the Association contre les Maladies Mitochondriales for their constant support.
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FOOTNOTES |
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