TY - JOUR
AU1 - Marin-Garcia,, Jose
AU2 - Goldenthal, Michael, J
AU3 - Moe, Gordon, W
AB - Energy metabolism, Heart failure, Mitochondria, Oxidative phosphorylation Time for primary review 34 days. 1 Introduction The heart is highly dependent for its function on oxidative energy generated in mitochondria, primarily by fatty acid β-oxidation, respiratory electron chain and oxidative phosphorylation (OXPHOS). In this review, we survey the available evidence that mitochondrial dysfunction may play a pivotal role in cardiac failure. We also discuss how mitochondrial dysfunction may be related to other critical cellular and molecular changes found in cardiac hypertrophy and failure, including dysfunctional structural and cytoskeletal proteins, apoptosis, calcium flux and handling, and signalling pathways. The review also focuses on the biochemical and molecular changes in severe heart failure secondary to primary cardiomyopathy (dilated/hypertrophic) in humans as well as findings in animal models of heart failure related to volume and/or pressure overload. 2 Mitochondria are the major source of bioenergy in the cell Mitochondria are abundant in energy-demanding cardiac tissue constituting 20–40% of cellular volume (greater proportion than in skeletal muscle). Mitochondrial energy production depends on genetic factors which modulate normal mitochondrial function including enzyme activity and cofactor availability and on environmental factors including the availability of fuels (e.g. sugars, fats and proteins) and oxygen. Fatty acids are the primary energy substrate for heart muscle ATP generation by OXPHOS and the mitochondrial respiratory chain, the most important supply of cardiac energy. The supply of ATP from other sources, e.g. glycolytic metabolism is limited in normal cardiac tissue. Fatty acid β-oxidation and the oxidation of carbohydrates through the TCA cycle generate the majority of intramitochondrial NADH and FADH which are the direct source of electrons for the electron transport chain (and produce as well a small proportion of the ATP supply) (Fig. 1) [1]. The heart also maintains stored high-energy phosphates (e.g. ATP and phosphocreatine pools). Fig. 1 Open in new tabDownload slide Mitochondrial bioenergetic pathways in cardiac failure. Mitochondrial inner-membrane localized respiratory complexes I–V (hatched circles) with associated electron-transfer components, CoQ and Cyt c, are depicted as are the matrix-localized NADH and acetyl CoA-generating fatty acid β-oxidation and TCA cycle pathways. Several inner-membrane transporters (white circles) for carnitine/fatty acids, the ATP/ADP and pyruvate carriers are shown. Key markers of apoptotic processes (solid circles) are shown including Cyt c, BCL-2 in the outer membrane, and matrix-localized mitochondrial superoxide dismutase (SOD). Fig. 1 Open in new tabDownload slide Mitochondrial bioenergetic pathways in cardiac failure. Mitochondrial inner-membrane localized respiratory complexes I–V (hatched circles) with associated electron-transfer components, CoQ and Cyt c, are depicted as are the matrix-localized NADH and acetyl CoA-generating fatty acid β-oxidation and TCA cycle pathways. Several inner-membrane transporters (white circles) for carnitine/fatty acids, the ATP/ADP and pyruvate carriers are shown. Key markers of apoptotic processes (solid circles) are shown including Cyt c, BCL-2 in the outer membrane, and matrix-localized mitochondrial superoxide dismutase (SOD). Myocyte ATP is needed and utilized by actomyosin ATPase and various ion pumps during contraction and relaxation in cardiac cells. Moreover, decreased cellular ATP levels (due to mitochondrial dysfunction) can markedly lower the threshold of plasma membrane depolarization [2] and therefore potentially influence impulse generation and conduction in the myocardium. 3 What is the evidence for myocardial dependency on mitochondrial function? 3.1 Mitochondrial dysfunction and cardiomyopathy: support from human studies Evidence of discrete mitochondrial OXPHOS defects or deficiency have been documented in cardiomyopathies. Both dilated (DCM) and hypertrophic cardiomyopathies (HCM) are frequently accompanied by changes in OXPHOS/respiratory enzyme activities [3–6]. A number of cardiomyopathies (most frequently HCM) have been shown to be primarily due to specific pathogenic point mutations in mitochondrial DNA (mtDNA) [7–14] shown in Table 1. The mtDNA mutations which are considered pathogenic are generally found in nucleotides which are highly conserved in evolution. These mutations are most frequently present in heteroplasmic fashion (a mixed population of both mutant and wildtype mtDNA genomes), and are usually accompanied by reduced levels of respiratory enzyme activity(s). A number of pathogenic mtDNA mutations identified in association with cardiomyopathy reside in mitochondrial tRNA genes (LEU, ILE, LYS, GLY). It has been recently proposed that the site of mutation within the generic tRNA cloverleaf may relate to the severity of the phenotypic effect and possibly to its tissue-specificity [15]. For example, clinically severe cardiomyopathies have been found in patients harboring similarly located mutations (e.g. 4269/9997 and 3303/8363). Pathogenic mutations in mitochondrial tRNA genes have been shown to negatively affect mitochondrial protein synthesis and specific respiratory enzyme activities. A cardiomyopathy-associated mtDNA mutation has also been found in mitochondrial rRNA (at nt 1555) [16]. Other mtDNA point mutations (some residing in tRNA genes, others residing in mtDNA protein-encoding or structural genes) have been found in patients with DCM in heart failure and were not present in normal individuals (also included in Table 1). These mtDNA mutations are heteroplasmic, and are present in highly conserved sequences [17–19, Marin-Garcia unpublished data]. Nevertheless, it remains to be determined whether these mutations are truly causative of cardiomyopathy. Table 1 Specific mtDNA point mutations in cardiomyopathy Gene . Site . AA change . Cardiac phenotype . Ref. . tRNA mutations Leu 3243 – DCM [24] A→G Leu 3260 – Tachycardia, [13] A→G adult onset Leu 3303 – Fatal infantile CM [9] C→T Ile 4300 – HCM- adult onset [14] A→G Ile 4317 – Fatal infantile CM [7] A→G Ile 4320 – Fatal infantile CM [10] C→T Ile 4269 – CF at 18 years, [8] A→G adult onset Lys 8363 – HCM [11] G→A Gly 9997 – Ventricular arrhythmia [12] T→C HCM Ala 5587 – DCM [19] T→C Arg 10415 – DCM [19] T→C Arg 10424 – Fatal DCM MGa T→C Structural gene mutations Cytb 14927 Thr→Ala DCM [17] A→G HCM MG Cytb 15236 Ile→Val DCM MG A→G Cytb 15508 Asp→Glu DCM MG C→G Cytb 15509 Asn→His Fatal post-partum CM MG A→C COI 6860 Lys→Asn DCM [19] A→C COII 7923 Tyr→Cys DCM MG A→G COIII 9216 Gln→Glu DCM MG A→G ND5 14069 Ser→Leu DCM MG C→T ATPase6 8993 Leu→Arg Leigh syndrome/HCM MG T→G Gene . Site . AA change . Cardiac phenotype . Ref. . tRNA mutations Leu 3243 – DCM [24] A→G Leu 3260 – Tachycardia, [13] A→G adult onset Leu 3303 – Fatal infantile CM [9] C→T Ile 4300 – HCM- adult onset [14] A→G Ile 4317 – Fatal infantile CM [7] A→G Ile 4320 – Fatal infantile CM [10] C→T Ile 4269 – CF at 18 years, [8] A→G adult onset Lys 8363 – HCM [11] G→A Gly 9997 – Ventricular arrhythmia [12] T→C HCM Ala 5587 – DCM [19] T→C Arg 10415 – DCM [19] T→C Arg 10424 – Fatal DCM MGa T→C Structural gene mutations Cytb 14927 Thr→Ala DCM [17] A→G HCM MG Cytb 15236 Ile→Val DCM MG A→G Cytb 15508 Asp→Glu DCM MG C→G Cytb 15509 Asn→His Fatal post-partum CM MG A→C COI 6860 Lys→Asn DCM [19] A→C COII 7923 Tyr→Cys DCM MG A→G COIII 9216 Gln→Glu DCM MG A→G ND5 14069 Ser→Leu DCM MG C→T ATPase6 8993 Leu→Arg Leigh syndrome/HCM MG T→G a Marin-Garcia, unpublished findings. Open in new tab Table 1 Specific mtDNA point mutations in cardiomyopathy Gene . Site . AA change . Cardiac phenotype . Ref. . tRNA mutations Leu 3243 – DCM [24] A→G Leu 3260 – Tachycardia, [13] A→G adult onset Leu 3303 – Fatal infantile CM [9] C→T Ile 4300 – HCM- adult onset [14] A→G Ile 4317 – Fatal infantile CM [7] A→G Ile 4320 – Fatal infantile CM [10] C→T Ile 4269 – CF at 18 years, [8] A→G adult onset Lys 8363 – HCM [11] G→A Gly 9997 – Ventricular arrhythmia [12] T→C HCM Ala 5587 – DCM [19] T→C Arg 10415 – DCM [19] T→C Arg 10424 – Fatal DCM MGa T→C Structural gene mutations Cytb 14927 Thr→Ala DCM [17] A→G HCM MG Cytb 15236 Ile→Val DCM MG A→G Cytb 15508 Asp→Glu DCM MG C→G Cytb 15509 Asn→His Fatal post-partum CM MG A→C COI 6860 Lys→Asn DCM [19] A→C COII 7923 Tyr→Cys DCM MG A→G COIII 9216 Gln→Glu DCM MG A→G ND5 14069 Ser→Leu DCM MG C→T ATPase6 8993 Leu→Arg Leigh syndrome/HCM MG T→G Gene . Site . AA change . Cardiac phenotype . Ref. . tRNA mutations Leu 3243 – DCM [24] A→G Leu 3260 – Tachycardia, [13] A→G adult onset Leu 3303 – Fatal infantile CM [9] C→T Ile 4300 – HCM- adult onset [14] A→G Ile 4317 – Fatal infantile CM [7] A→G Ile 4320 – Fatal infantile CM [10] C→T Ile 4269 – CF at 18 years, [8] A→G adult onset Lys 8363 – HCM [11] G→A Gly 9997 – Ventricular arrhythmia [12] T→C HCM Ala 5587 – DCM [19] T→C Arg 10415 – DCM [19] T→C Arg 10424 – Fatal DCM MGa T→C Structural gene mutations Cytb 14927 Thr→Ala DCM [17] A→G HCM MG Cytb 15236 Ile→Val DCM MG A→G Cytb 15508 Asp→Glu DCM MG C→G Cytb 15509 Asn→His Fatal post-partum CM MG A→C COI 6860 Lys→Asn DCM [19] A→C COII 7923 Tyr→Cys DCM MG A→G COIII 9216 Gln→Glu DCM MG A→G ND5 14069 Ser→Leu DCM MG C→T ATPase6 8993 Leu→Arg Leigh syndrome/HCM MG T→G a Marin-Garcia, unpublished findings. Open in new tab In addition to cardiomyopathies, many cases of systemic mitochondrial diseases with cardiac involvement have been reported. These disorders tend to have a wide spectrum of neurological manifestations. Some are maternally inherited (due to mtDNA mutation) and may present a variable cardiac phenotype (ventricular hypertrophy, cardiomegaly and dysrhythmias) [20–22]. Examples include Leigh, MELAS and MERRF syndromes. One of the many puzzling aspects of the field of mtDNA pathogenesis concerns the frequently reported observation that specific mtDNA mutations found in association with primary cardiomyopathy can also be found in patients with quite different arrays of neurological disorders. For instance, the 8363 mutation has been found in several cases of HCM and the same mutation has also been detected in patients (and family members) with severe encephalomyopathies including Leigh syndrome [23], ataxia or sensorineural deafness with or without the cardiomyopathy [11]. Similarly, a mutation at nt 3423 in tRNALEU (probably the most characterized and frequently found tRNA mutation reported in mitochondrial disorders) which has been only associated with MELAS phenotype was recently found in cases of isolated cardiomyopathy with no systemic manifestations [24]. A potential explanation for this puzzle correlating genotypic mutation to phenotypic manifestation, is the involvement of other genetic or environmental co-factor(s) which may modulate the effect of mtDNA mutations. In addition to maternally inherited disorders, some of the mitochondrial disorders with cardiac manifestations are sporadic (in general, due to somatic large-scale mtDNA deletions) including Kearns–Sayre syndrome (KSS) in which patients may display cardiomyopathy and cardiac conduction abnormalities. The majority of KSS mtDNA deletions are of a single type, not inherited, and have been found primarily in skeletal muscle [25]. In contrast, autosomal nuclear loci are thought to be the cause of multiple mtDNA deletion phenotypes. However, the precise genetic defect has not yet been identified [26] and can be either dominantly or recessively inherited [27,28]. The mtDNA deletion events detected in KSS and in autosomal disorders tend to be highly abundant (ranging up to 95% of the total mtDNA) either as single-sized discrete deletions or in the aggregate [17]. Due to their abundance, these deletions are often detected by southern blot analysis. A second type of large-scale mtDNA deletion event (usually found at specific sites) has been found in cardiac tissue of many primary cardiomyopathies. These mtDNA deletions tend to be less abundant (<0.1%) and are often only detectable by PCR analysis. Their significance in cardiac pathogenesis is not yet clear; they may be evidence of specific mtDNA damage and tend to occur in an age dependent manner [29–31]. Whether mtDNA deletion events are primary to cardiomyopathic disease or whether they represent secondary somatic mutations arising from cardiac dysfunction and resulting metabolic changes (e.g. increased oxygen free radical-mediated damage to mtDNA) remains unresolved [17,29]. Evidence of the relationship of cardiac cellular damage and mtDNA mutations has been further confirmed from cybrid experiments. Experiments with mutant alleles at nt 3243, 3260 and 9997 [32–34] show that cells harboring these mutations have diminished mitochondrial protein synthesis and respiratory enzyme activity(s). Similarly, deletions in mtDNA have also been shown to adversely effect mitochondrial protein synthesis and respiratory function(s) in cells in which they have been introduced [35]. A limitation of these type of studies (which involve single cells in culture) is that they only confirm that there is a relationship between a defect in mtDNA and mitochondrial dysfunction but not necessarily with the cardiac dysfunction/phenotype. Cardiac mtDNA depletion has also been noted in cardiomyopathy. DCM occurs in patients treated with AZT [36,37]. Depletion of mtDNA levels is specifically induced by zidovudine (AZT), which inhibits both the DNA polymerase of the HIV-virus and DNA polymerase gamma (mtDNA polymerase). Reduced mtDNA levels with concomitant reduction in respiratory activities were found in both patients and animals treated with zidovudine [36]. Depletion of mtDNA levels has been found in cardiac tissues of an isolated case of severe HCM with reduced cardiac respiratory activities [38]. Moreover, reduced mtDNA levels have been found in skeletal muscle of patients with cardiomyopathy [39] as well as in patients with myopathy. In one study of the neuropathies associated with skeletal muscle mtDNA depletion, a direct relationship of levels of mitochondrial transcription factor A (mt-TFA) to mtDNA levels was suggested [40]. However, no evidence of reduced levels in cardiac mt-TFA levels was found in the study of cardiomyopathic patients with cardiac mtDNA depletion [38]. 3.2 Nuclear mutations in mitochondrial components Mutations in a wide spectrum of nuclear genes encoding mitochondrial proteins also can cause cardiomyopathy. For example, mutations in mitochondrial transport proteins (e.g. carnitine-acylcarnitine translocase) which facilitate passage of critical metabolites across the inner mitochondrial membrane have been shown to be involved in cardiomyopathy [41]. Friedreich ataxia (which often presents with HCM) is caused by mutations in a mitochondrial transport protein, frataxin, thought to be involved in iron accumulation [42,43]. It has been recognized for some time that deficiencies in the fatty-acid β-oxidation pathway can also lead to cardiomyopathy. For example, defects in the gene encoding very long chain acyl-Co A dehydrogenase (VLCAD) [44] as well as in long chain 3-hydroxylacyl CoA dehydrogenase have been reported to be a cause of fatal cardiomyopathy in young children [45]. Other defects in carnitine metabolism have been shown to cause pediatric cardiomyopathy [46]. In these patients, carnitine supplementation can be of considerable therapeutic value. Potential causes of many of the inherited disorders of fatty acid β-oxidation and carnitine metabolism include inadequate supply of NADH and energy to the heart [1] and the accumulation and pathophysiological effects of toxic levels of fatty free acids on cardiac function. 3.3 Support from animal models There is increasing evidence from mouse transgenic models that disruption in mitochondrial bioenergy at specific loci or pathways can cause cardiomyopathy and cardiac failure. Gene ablation (i.e. ‘knock-out’ mutations) in genes encoding the adenine nucleotide translocator (ANT), mitochondrial Mn2+-superoxide dismutase and most recently, mt-TFA, lead to phenotypic DCM and cardiac failure [47–49]. Only the latter mutation could be said to have a direct effect on OXPHOS and respiratory complex activities since disruption of mtTFA strongly reduces mtDNA gene expression. The ‘knock-out’ approach has not yet been accomplished with mtDNA genes due to the formidable technical difficulty involved in direct gene-replacement or gene-ablation of a multi-copy gene in the setting of a non-nuclear multi-copy organelle (i.e. the mitochondrion). The range of mutant genes capable of causing cardiomyopathies appears rather broad. In addition, there are indications that mitochondrial function can be altered in animal models of cardiac hypertrophy and failure by down-regulation of expression of fatty acid utilization enzymes [50]. 3.4 Other cellular/molecular events in cardiac failure Numerous molecular and cellular changes leading to cardiac failure have been identified thus far. The reader is referred to an excellent review on this subject [51]. Historically, investigation has centered on the changes in the cardiac pump by examining disturbances in calcium flux/homeostasis, and in levels of major contractile proteins (e.g. myosin, actin, ATPase and troponin) [52]. More recently, focus has shifted to the hypertrophic growth and myocardium-remodelling stimuli, the elucidation of signal transduction pathways leading to cardiac hypertrophy and failure, the role of apoptosis in heart re-modelling and the extra-cellular matrix/cytoskeletal changes occurring in cardiac failure [53]. Primary mutations in structural sarcomeric and cytoskeletal proteins have been identified in specific cases of cardiomyopathy leading to cardiac failure. These tend to be inherited in a Mendelian fashion (generally autosomal dominant). Some of these changes have been found to be due to specific mutations in nuclear DNA-encoded structural genes. A high percentage of cases of familial hypertrophic cardiomyopathy (FHCM) appear to be due to mutations in myofibrillar proteins involved in the generation of force including β-myosin heavy chain (β-MHC), cardiac troponin T, α-tropomyosin and myosin-binding protein C [54–57]. The best characterized mutations reside in β-MHC [54] and a number of these mutations are associated with poor prognosis (including sudden death). Other β-MHC mutations are associated with more moderate cardiac phenotype(s). While the extent of hypertrophy in these patients is often generally mild, they exhibit a high frequency of early sudden death. Genes encoding important structural and cytoskeletal proteins have also recently been implicated in the pathogenesis of other types of cardiomyopathy. These proteins (e.g. actin) organize the contractile apparatus of cardiac myocytes and in some cases (e.g. dystrophin, sarcoglycan) anchor the myocytes in their extracellular milieu allowing the generation of force [53]. Mutations in the cardiac actin gene have been found in patients with familial DCM [58]. Mutations in the δ-sarcoglycan gene have been identified as the molecular defect responsible for the autosomal recessive cardiomyopathy found in the Syrian hamster [59]. Defects in the gene encoding dystrophin have been identified as causal in the X-linked DCM and cardiac failure associated with Duchenne syndrome [60]. Recent studies have also identified specific point mutations as well as a null allele in the gene for desmin, a major myofibrillar structural protein involved in linking Z bands to the plasma membrane resulting in several cases of both cardiomyopathy and skeletal myopathy [61]. In cardiac failure, changes in Ca2+ transport and metabolism have also been found. At the molecular level, marked reductions in the levels of phospholamban mRNA and both sarcoplasmic reticulum Ca2+-ATPase mRNA and enzyme activity, as well as increased levels of sarcolemmal Na+-Ca2+ exchanger [62] have been reported [62–65]. At the physiological level there is a prolonged action potential and Ca2+ transient, decreased Ca2+ uptake and reduced Ca2+ release by the sarcoplasmic reticulum and increased diastolic Ca2+ concentration [52]. It is not yet clear whether these are primary or secondary changes to other events in cardiac failure. Apoptotic processes have been shown to be pivotally involved in the heart re-modelling which accompanies or precedes heart failure. Myocardial apoptosis has been documented in patients with end-stage DCM [66,67]. Critical issues that remain to be elucidated include identification of the molecular triggers for cardiac apoptosis, the precise quantification of apoptotic cells and data concerning the time of apoptosis onset and completion. The overall role of apoptosis in cardiac failure (while highly attractive as a theoretical construct) is not yet known [67]. Findings from in vitro systems and animal models suggest that myocardial apoptosis occurs in response to a variety of insults including ischemia–reperfusion, myocardial infarction, pacing, mechanical stretch and aortic constriction-pressure overload. Factors present in the failing myocardium, shown to cause or be involved with apoptosis, include catecholamines, angiotensin, inflammatory cytokines, reactive oxygen species, nitric oxide, hypoxia, peptide growth factors (e.g. TGF and cardiotrophin) and mechanical stress. A subset of these factors also mediate hypertrophy of cardiac myocytes in vitro [51,68,69]. 4 To what extent do cellular and molecular changes associated with mitochondria contribute to cardiac failure? A number of the aforementioned cellular/molecular changes observed during cardiac failure involve mitochondria and bioenergetic production. However, this relationship has not been fully investigated and requires further exploration. It could be argued that mitochondrial dysfunction plays an integral part in the mechanism of cardiac dysfunction, even when other factors are more evident or it may represent a common downstream event in the pathways leading to cardiac failure. In most cases of cardiac failure, it remains to be established whether the mitochondrial abnormalities associated with other myocardial changes discussed below are truly primary or secondary to other abnormalities in myocardium (e.g. hypertrophy, remodelling etc.) as compared to the less-speculative nature of the mitochondrial defects in the cases of primary mitochondrial dysfunction discussed previously (e.g. those featured in Table 1). In addition, studies are critically needed to gauge the extent that mitochondrial abnormalities (either primary or secondary to other myocardial changes) contribute to the pathophysiology of cardiac function. 4.1 Mitochondrial function and cardiac hypertrophy Cardiac hypertrophic changes have been associated with increased mitochondrial number and size [70] as well as increased mtDNA synthesis [71]. Early studies of rat cardiac hypertrophy found a co-ordination between complex IV activity, nuclear-encoded mRNA and mitochondrial rRNA synthesis. Within 24 h after growth stimulus, a specific decrease was found only in mitochondrial mRNA synthesis [72]. Thyroid hormone can affect mitochondrial structure and function. For instance, thyroid hormone treatment causes cardiac hypertrophy similar to aortic stenosis in rats [72]. Both models of cardiac hypertrophy show increases in total tissue RNA accompanying increases in ventricular weight as well as in both cytosolic and mitochondrial ribosomes. Thyroxin can also modulate increases in mitochondrial enzyme activities [73]. It has been proposed that regulation is exerted at the level of transcriptional regulation of nuclear genes encoding mitochondrial proteins (including components of the respiratory pathway). This regulatory effect may occur as a result of many of the nuclear-encoded mitochondrial genes having thyroxin-sensitive promoter elements. 4.2 Mitochondrial function and structural/cytoskeletal protein defects Mutations in structural proteins can be accompanied by mitochondrial dysfunction as shown by a recent study of transgenic mice harboring a missense allele of cardiac troponin T [56]. This study further suggested that there are likely allele-specific mechanisms in the cellular pathogenesis of cardiomyopathy which may partially explains its heterogeneity. Another recent report showed that patients with HCM can harbor pathogenic mutations in both β-MHC and in mtDNA [74]. It remains to be determined whether the combination of both mutant alleles in β-myosin and mtDNA make HCM more likely, and how this pathogenic combination might influence the disease's severity and time-course. Patients with β-MHC mutations often contain an abundance of type 1 fibres in skeletal muscle which lack mitochondria at their core [75]. Moreover, marked reduction in mitochondrial function in patients with β-MHC mutations was further borne out by studies showing a marked decrease in oxidative capacity in muscle [76]. Also, the intracellular distribution of mitochondria could be altered in patients with defective structural proteins since both the intracellular position and movement of mitochondria are known to be mediated by cytoskeletal proteins. The cellular location of mitochondria and its potential effect on mitochondrial function during cardiomyopathy and cardiac failure warrant further study likely using an in situ approach. 4.3 Calcium signalling and mitochondrial function in cardiac failure Mitochondria may play a regulatory role as a sensor of intracellular free Ca2+[77]. Several mechanisms of enhanced function of OXPHOS by Ca2+ have been reported including: (a) stimulation of several dehydrogenases in the TCA cycle due to increases in mitochondrial matrix Ca2+[78]. (b) Activation by Ca2+ of mitochondrial ATP synthase activity [79,80]. Acute cardiac failure generated by manipulating calcium concentrations in perfused canine hearts was accompanied by a striking decrease in mitochondrial respiratory function [81]. The methodologies for investigating mitochondrial pool sizes and fluxes of Ca2+ using fluorescent dyes have been markedly improved and should be evaluated relative to mitochondrial respiratory activities. 4.4 Mitochondrial function and apoptosis in cardiac failure Many of the major apoptotic proteins are located in mitochondria and may impact on mitochondrial function. For instance, the oncogenic protein BCL-2, a well-established marker of apoptosis is located in the mitochondrial outer-membrane. However, although well-characterized in cell culture apoptosis models, evidence supporting a definitive role of BCL-2 in human/rat cardiac apoptosis studies has been at best, equivocal. Cytochrome c (a key component of the electron-transport chain) is released from mitochondria in association with the activation of caspase-3 and a series of proteases that are critical to cellular breakdown and programmed cell death. Many recent studies have identified this event as a key hallmark and critical signalling event of apoptosis. Recently, cytochrome c release from mitochondria was found to also occur in the failing human heart and cardiomyopathy [82]. However, to the best of our knowledge, there are no rigorous studies of mitochondrial OXPHOS during cardiac failure-associated apoptosis. Reactive oxygen species (ROS) has been implicated in apoptosis induction [83,84]. Evidence has been also presented that the generation of free O2 radicals comes largely from hypoxic mitochondria and from respiratory dysfunction. In addition, mitochondrial-located superoxide dismutase which has a pivotal role in regulating the accumulation of free radicals appears to also be a contributory factor in apoptosis. 4.5 Other mitochondrial enzymes in cardiac failure In a canine model of pacing-induced heart failure that closely mimics human cardiomyopathy, myocardial tissues from paced dogs had markedly reduced activities of myofibrillar Ca2+ ATPase, sarcoplasmic reticulum Ca2+ ATPase and mitochondrial ATP synthase. On the other hand, paced dogs had significantly higher activities of the fatty acid β-oxidation enzyme hydroxylacyl-CoA dehydrogenase and the Krebs cycle enzyme, oxoglutarate dehydrogenase. These data suggest that in pacing-induced heart failure, there is a impairment of a key ATP generating enzyme and downregulation of ATP-utilizing enzymes with a increase (possibly compensatory) in fatty acid oxidation and Krebs cycle activities [85]. The reduction in the levels of myocardial mitochondrial ATP synthase activity was further identified as both an early and a persistent event in the development of cardiac failure [86]. Similar findings of reduced levels of mitochondrial ATP synthase activity were also reported in a naturally occurring canine model of idiopathic dilated cardiomyopathy [87]. Several models of mechanically overloaded heart have presented further evidence of alteration in mitochondrial bioenergetics and left ventricle dysfunction in cardiac failure. In both volume- and pressure-overloaded rat hearts [88], depletion of phosphocreatine occurs in left ventricular hypertrophy. Patients in cardiac failure [89] have shown marked reductions in levels of phosphocreatine (similarly decreased in HCM and DCM). Reduced mitochondrial creatine kinase activity and content were also demonstrated in a rat pressure-overload model [90]. In volume-overloaded hypertrophied hearts, alterations in myocardial high energy phosphate (i.e. significantly lower myocardial creatine phosphate/ATP ratios) have been postulated to contribute to contractile/pump dysfunction occurring during exercise [91]. Interesting, these mitochondrial abnormalities in function persisted despite adequate tissue oxygenation [92] and suggest that altered regulation of mitochondrial oxidative phosphorylation results in the reduced phosphocreatine levels observed in cardiac failure [93]. Modulation of oxidative phosphorylation activities could be achieved by differential substrate utilization, changes in ADP, inorganic phosphate, intramitochondrial NADH and oxygen levels [94]. In recent studies using a porcine model of left ventricular infarction and remodelling induced by ligation of the left circumflex artery, reduced systolic performance accompanied by reductions in high energy phosphate levels, myocardial oxidative phosphorylation and concomitant reductions in the ANT protein carrier and in the β subunit of the mitochondrial ATP synthase were noted [95,96]. These studies suggest that specific mitochondrial inner-membrane proteins may play a critical role during the myocardial remodelling that occurs in cardiac failure. The order of molecular and biochemical events leading to an altered regulation of oxidative phosphorylation needs to be established. 5 What events occurring in cardiac failure are truly tissue-specific? The finding of shared events in skeletal muscle and heart during cardiac failure has considerable prognostic implication for the clinician. Yet to date, despite (and possibly because) of the immense research effort in this area, the relationship between cardiac and skeletal muscle events in heart failure at the cellular and molecular levels has not been comprehensively examined. In this review, we provide a brief overview of molecular and cellular changes in cardiac and skeletal muscle focusing on the bioenergetic/mitochondrial events in both tissues. A number of changes occur in skeletal muscle during cardiac failure. Histological and electromyographic evidence of generalized myopathy and exercise intolerance are often present. Evaluation of skeletal muscle metabolism by the non-invasive methodology of phosphorus nuclear magnetic resonance spectroscopy demonstrated altered levels of phosphocreatine and inorganic phosphate in patients with heart failure following moderate exercise [97,98]. Patients with desmin and β-MHC mutations known to cause HCM and cardiac failure have defined changes in skeletal muscle fibers; patients with specific β-MHC mutations may develop abnormal mitochondrial number and function in skeletal muscle [75,76] as well as type I fiber abnormalities and atrophy [99]. Congestive heart failure is often accompanied by skeletal myopathy with a shift from slow aerobic fatigue-resistant fibers to fast anaerobic ones. Is the fiber atrophy mediated by apoptosis? Evidence of apoptosis as gauged by TUNEL, as well as significantly reduced expression of BCL-2 has been demonstrated in both skeletal muscle tissues of patients with chronic heart failure [100] and from rats with experimentally-induced heart failure [101]. Interestingly, evidence of increased iNOS was also noted in the patients with cardiac failure. Structural and functional changes in skeletal muscle mitochondria have also been found in cardiomyopathy/cardiac failure [102,103]. In addition, pathogenic mtDNA mutations (e.g. 3243, 3260, 4269, 8344, 8363, 9997) present in cardiomyopathy with a broad spectrum of myopathies and accompanying respiratory enzyme defects, are present at relatively high levels in skeletal muscle. Moreover, the use of skeletal muscle biopsies (instead of endomyocardial biopsy) for analysis of respiratory enzyme dysfunction has been recommended in the diagnostic evaluation of mitochondrial-mediated cardiac abnormalities [104]. Recently, reductions in specific enzyme activities were found in both skeletal and cardiac muscle in a group of children with cardiomyopathy [104]. Similarly, pronounced complex IV defects were shown in both cardiac and skeletal muscle of patients with KSS and cardiomyopathy [105]. In some patients, the mitochondrial dysfunction is treatable by supplementation with vitamins, coenzyme Q and/or carnitine. While an increasing incidence of cardiac mtDNA deletions in patients with DCM has been reported [28–31], scarce data are available regarding the tissue-specificity or correlation of the extent of cardiac mtDNA deletions with skeletal muscle deletions in the same patient. In isolated cases of KSS with cardiomyopathy, both skeletal muscle and heart harbored high amount of mtDNA deletion [106]. Also, multiple mtDNA deletions have been detected in skeletal muscle of patients with cardiomyopathy. However, it remained unknown whether deletions were present in cardiac tissue since cardiac biopsies were not available [27, Marin-Garcia, unpublished data]. Similarly, patients with decreased levels of cardiac mtDNA have not been studied with regards to the levels of skeletal muscle mtDNA. Patients with both cardiomyopathy and myopathy have been reported to contain skeletal muscle mtDNA depletion (not investigated in heart) [39]. The forementioned effects of AZT on mtDNA levels, respiratory complex activities and on phenotype were found in both heart and skeletal muscle from human and animal models [36]. In summary, many of the cellular cardiac changes as well as mitochondrial abnormalities often revealed during cardiac failure appear to be present in skeletal muscle. While more evidence confirming these findings is warranted, evaluation of skeletal muscle mitochondrial function could be helpful in the overall diagnostic and prognostic evaluation of cardiac failure. To determine what other parts of the cardiac failure signalling-pathway are truly cardiac specific and which might be also operative in skeletal muscle awaits further studies. Such studies might shed light about the relationship between the signalling pathway(s) and mitochondrial energetics. 6 Future prospects The use of transgenic mice with defined mutations to study their impact and relationship to cardiac failure has been very informative. However, at present there still remains a gap in information about the physiological, biochemical and molecular events in normal mouse heart. What is needed is a rigorous standardization of quantitative measurements relevant to mitochondrial bioenergetics, structure and function in both cardiac and skeletal muscle tissues. This should include an evaluation of the levels of mitochondrial enzyme activities, mtDNA, ATP, ADP and NADH, as well as the comprehensive investigation of mitochondrial changes (including mtDNA deletions) as a function of age. Particular focus should be directed to the activity levels and content of mitochondrial ATP synthase and ANT, given the degree to which they appear affected in cardiac failure. Such information should provide the requisite database, to investigate and compare the direct effects of introducing mutant genes in animal model (e.g. mouse) to test for pathogenic mutations that effect both mitochondria and cardiac function. 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TI - Mitochondrial pathology in cardiac failure
JF - Cardiovascular Research
DO - 10.1016/S0008-6363(00)00241-8
DA - 2001-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/mitochondrial-pathology-in-cardiac-failure-IAERX7LNR7
SP - 17
EP - 26
VL - 49
IS - 1
DP - DeepDyve
ER -