August 2010 | Vol 7 | N.º 8 | CNIC-23 [ PDF (864 KB)]

Cardiopathies of mitochondrial origin

Erika Fernández-Vizarra, María Pilar Bayona-Bafaluy and José Antonio Enríquez*
Correspondence to:
J. A. Enríquez, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), C/ Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Email jaenriquez@cnic.es

Competing interests
The authors declare no competing interests.

ABSTRACT
Mitochondrial disease is characterised by a malfunction of the oxidative phosphorylation (OXPHOS) system. This is a heterogeneous group of genetic disorders that, owing to the dual genome origin of the system, can be caused by mutations in either mitochondrial DNA or nuclear DNA. Clinical presentation is usually of neuromuscular illness. However, cardiomyopathy, either alone or in combination with other symptoms, is also found very frequently. In this review we illustrate the mitochondrial alterations that have been described as the primary cause of cardiomyopathy.

INTRODUCTION: MITOCHONDRIAL DISORDERS AND MITOCHONDRIAL GENETICS
Taken together, mitochondrial disorders or, more precisely, disorders of the mitochondrial oxidative phosphorylation (OXPHOS) system, are some of the most frequent inherited metabolic disorders with an estimated incidence of 1 in 5,000 live births.¹ The mitochondrial OXPHOS system (Figure) uses its four respiratory chain complexes (Complex I, II, III and IV) and the ATP synthase (Complex V) to produce energy, i.e., synthesise ATP, in eukaryotic cells. This is a unique process in the cell because OXPHOS biogenesis depends on two physically separated genomes: nuclear DNA and mitochondrial DNA (mtDNA). Mitochondria contain their own genetic material and are an example of extreme genetic information compactness, as only a small proportion of its 16,569 bp sequence (in humans) is non-coding (Figure). However, the 13 polypeptides encoded by the mtDNA are essential components of the OXPHOS system as they constitute core or catalytical subunits of Complexes I, III and IV or are needed for the assembly of Complex V. Moreover, mammalian mtDNA also contains 22 tRNAs and 2 rRNAs required for the expression of the aforementioned structural subunits. Nevertheless, the rest of the complexes’ structural subunits and numerous other proteins necessary for the expression of mtDNA and for other processes involved in OXPHOS system biogenesis are encoded in the nucleus, translated in the cytoplasm and imported into the organelle where they exert their specific function. Considering the inherent complexity of bringing together this system, the origin of OXPHOS disorders is also complicated. These disorders can originate from mutations in the mtDNA, which has a maternal inheritance pattern, or by mutations in nuclear genes encoding mitochondrial proteins, which can have autosomal recessive, dominant or X-linked inheritance. When dealing with mtDNA genetics, one has to bear in mind that thousands of mtDNA molecules are present in each cell, leading to the concepts of homoplasmy, where all copies of mtDNA are the same, and heteroplasmy, where several types of mtDNA (i.e., mutant and wild-type molecules) coexist in the same cell. Normally, in heteroplasmic cases, the pathological phenotype is expressed when a certain percentage of mutant mitochondrial DNA (threshold) is reached.² There are many examples in the literature of mitochondrial disorders of different genetic origin (see the MITOMAP³ database: www.mitomap.org), and some exhaustive reviews have recently been published.^2,4-6 These diseases are clinically heterogeneous, there is a loose correlation between genotype and phenotype and they can affect any tissue, as failure in ATP production will cause malfunction in any cell. Thus, in many cases the clinical presentation is a multi-system disorder, although the most frequent presentations are neurological, affecting mostly the central nervous system and peripheral nerves, with myopathy also being very common. However, conduction defects or cardiomyopathy are usual features of OXPHOS disorders^7-11 and cardiological exploration is recommended when clinically assessing the possibility of mitochondrial disease.^11-13

CARDIOPATHIES DUE TO MUTATIONS IN mtDNA
The pathological changes found in mtDNA that are associated with clinical phenotypes can be classified into three main categories: 1) point mutations that can affect either protein synthesis genes (rRNAs and tRNAs) or mtDNA-encoded structural OXPHOS subunits; 2) re-arrangements, which can be single or multiple deletions (where a fragment of the mtDNA molecule is lost) or partial sequence duplications and 3) depletions, in which the amount of mtDNA is low. It has been observed that although these mtDNA defects are not often associated solely with cardiomyopathy, they have serious effects on cardiac tissue because ATP derived from OXPHOS is essential for maintaining the heart’s contractile activity. In this regard, after the encephalo-neuromuscular syndromes, cardiomyopathy is the most common pathological phenotype associated with mtDNA point mutations,5 with an estimated 20% associated with cardiac phenotypes, predominantly hypertrophic cardiomyopathy.¹⁴

Point mutations in mitochondrial protein synthesis genes associated with cardiomyopathy
Most of the pathological mutations in mtDNA are located in tRNA genes, which are usually associated with a reduction of OXPHOS enzyme activities due to a general decrease in mitochondrial protein synthesis. Thus, in most cases, the biochemical findings are Complex I + Complex IV combined deficiencies.
Point mutations in MT-TL1 (OMIM 590050):15 The heteroplasmic m.3243A>G transition within the tRNALeu(UUR) gene is one of the most recurrent pathological mtDNA changes and is the principal mutation associated with MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome (OMIM 540000). Although MELAS syndrome is predominantly a neurological disease, patients with this disease are particularly prone to cardiomyopathy.¹¹ Thus, cardiac involvement revealed by left ventricle hypertrophy, Wolf-Parkinson-White syndrome or pulmonary artery hypertension has been observed in 38% of patients suffering from this disorder,16 with hypertrophic cardiomyopathy being the most frequent cardiac manifestation in MELAS. ^7-8
The heteroplasmic m.3260A>G transition is less frequent and has been associated with maternally inherited or mitochondrial myopathy and cardiomyopathy (MIMyCa), which was originally described in a large Italian pedigree who presented impaired cardiac ejection fraction and, in some individuals, severe hypertrophic cardiomyopathy and even Wolf-Parkinson-White syndrome.¹⁷ The pathogenicity of the mutation was further confirmed by the appearance of a second family¹⁸ with the same clinical phenotype and by studying cultured cells whose mtDNA bore this mutation.¹⁹
The m.3303C>T mutation tRNALeu(UUR) gene should also be considered in the differential diagnosis of infantile-onset cardiomyopathies because it has been found in patients presenting severe infantile cardiomyopathy.^20-21 However, it was also found in other individuals with moderate-severe cardiomyopathy and with isolated myopathy.²¹

Point mutations in MT-TI (OMIM 590045): The m.4269A>G mutation in the tRNAIle gene was originally described in a patient with mitochondrial encephalomyopathy who died at the age of 18 years because of progressive intractable heart failure.²² This mtDNA mutation was responsible for the impaired OXPHOS activities and oxygen consumption observed in cell culture.²³
Another pathological mutation in the same gene, m.4295A>G, was detected in a 7-month-old girl who died of complications of hypertrophic cardiomyopathy and in one of her brothers who was found to have concentric left ventricular hypertrophic cardiomyopathy, mild mitral regurgitations and reduced ejection fraction at 2 years of age.²⁴
The case of the m.4300A>G mutation deserves special attention in this review because the clinical phenotype and biochemical abnormalities were found exclusively in the heart. The mutation has been found in homoplasmy in two families with individuals suffering from maternally inherited hypertrophic cardiomyopathy,²⁵ highlighting the importance of MT-TI mutations as the cause of cardiomyopathy.
The m.4317A>G mutation was described in an infant with fatal cardiac failure, anaemia, metabolic acidosis and increased muscle enzymes who showed severe dilatation and hypertrophy of the left ventricle at necropsy.²⁶
Another mutation in the same gene, m.4320A>G, was found in a case of intractable hypertrophic cardiomyopathy and encephalopathy.²⁷
Point mutations in MT-TK (OMIM 590060): Mutations in the tRNALys have been consistently associated with myoclonic epilepsy associated with red ragged fibers (MERRF) syndrome (OMIM 545000), with 80-90% of cases associated with the m.8334A>G mutation. This, again, is mainly a neuromuscular disorder but some cases have been described in which the patients present clinical cardiomyopathy.⁸
The m.8348A>G mutation has been related to a case of cardiomyopathy with severe ultrastructural alterations of the mitochondria in cardiomyocytes. In this case, severe cardiomyocyte degeneration and deterioration from hypertrophic cardiomyopathy and severe dilated cardiomyopathy was observed.²⁸
Another mutation in this tRNA, the m.8363G>A transition, was associated with a syndrome consisting of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy without evidence of MERRF in two unrelated families.²⁹
Point mutations in MT-TG (OMIM 590035): A unique heteroplasmic m.9997T>C transition in the mitochondrial tRNAGly gene was found in a multiplex family who manifested nonobstructive cardiomyopathy.³⁰
Point mutations in MT-TH (OMIM 590040): An m.12192A>G mutation was found in a Japanese family with dilated cardiomyopathy.³¹ In the same study, 126 patients with hypertrophic cardiomyopathy, 55 patients with dilated cardiomyopathy and 168 control subjects without cardiac disease were screened. Four additional patients with the m.12192G>A substitution were identified: two had hypertrophic cardiomyopathy and the other two presented with dilated cardiomyopathy.
Point mutations in MT-TL2 (OMIM 590055): A heteroplasmic pathological mutation within the tRNALeu(CUN) gene, m.12297T>C, has been associated with clinical phenotypes of congestive heart failure with a high mutation load in the myocardium32 and has also been associated with dilated cardiomyopathy.³³
Point mutations in MT-RNR1 (OMIM 561000): The m.1555A>G change in the mitochondrial 12S ribosomal RNA has been associated mainly with a phenotype of aminoglycoside-induced deafness. However, it was also found in heteroplasmy in a family with maternally inherited restrictive cardiomyopathy.³⁴

Point mutations in the mitochondrial structural subunit genes associated with cardiomyopathy
Pathological changes in the sequence of the 13 polypeptide-encoding mtDNA genes have been reported mainly in infants with progressive encephalopathies and lactic acidosis ⁵ However, cardiac abnormalities have also been shown to be caused by mutations in these genes and are briefly discussed here.
Point mutations in Complex I structural subunits: Some mutations in the mitochondrial ND complex I subunits cause Leber hereditary optic neuropathy (LHON; OMIM 535000), which also often leads to cardiac conduction defects, with approximately 9% of these patients diagnosed with cardiac arrhythmia, primarily from pre-excitation syndromes.³⁵ Mutations in MT-ND5 (OMIM 516005), which encodes the ND5 subunit of respiratory chain Complex I are relatively frequent and, like mutations in the other mtDNA Complex I (ND) subunits, have been shown to be the main cause of MELAS and Leigh syndromes. However, the m.13513G>A mutation has also been associated with Wolff-Parkinson-White (WPW) syndrome and hypertrophic cardiomyopathy, in association with Leigh syndrome.³⁶ This report suggested that this particular mutation is an important factor in patients with Leigh syndrome associated with WPW syndrome and/or optic atrophy and that heart function monitoring by echocardiography is recommended for this group of patients.
Point mutations in Complex III structural subunits: MT-CYB (OMIM 516020) encodes the Cytochrome b subunit, which is the only one of the 11 proteins of the mitochondrial respiratory chain complex III that is encoded by mtDNA. Several mutations in this gene have been associated with LHON, encephalomyopathy and, most frequently, to exercise intolerance. Additionally, the m.15243G>A and the m.15498G>A mutations have been related to hypertrophic cardiomyopathy with maternal inheritance.^37-38 Another mutation, m.14849T>C, was identified as the cause of cardiomyopathy together with other pathological features in a more complex disease.³⁹
Point mutations in Complex V structural subunits: Mutations in the gene encoding subunit 6 of the ATP synthase, MT-ATP6 (OMIM 516060), have been reported in several studies as the cause of maternally inherited neuropathy–ataxia–retinitis pigmentosa (NARP) syndrome and Leigh syndrome. The most frequent mutation is m.8993T>G, which has also been associated with hypertrophic cardiomyopathy. In addition, the m.8528T>C transition was shown to be the cause of infantile isolated hypertrophic cardiomyopathy in four unrelated patients.⁴⁰ This mutation not only affected the initiation codon of MT-ATP6 but also produced a drastic amino acid change in the sequence encoding MT-ATP8 (OMIM 516070), the other mtDNA-encoded Complex V subunit, which has overlapping sequences with MT-ATP6 (Figure). Another mutation in the ATP8 subunit (m.8529G>A) was found in a 16-year old patient presenting with apical hypertrophic cardiomyopathy and neuropathy.⁴¹

MtDNA rearrangements associated with cardiopathy
Single partial deletions, in which the mtDNA molecule loses a portion of 1.3 to 8 kb, are among the most frequent mutations in mtDNA. They usually occur sporadically and always coexist with variable amounts of wild-type mtDNA.2,5 When multiple mtDNA deletions are found in the affected tissues, this is normally due to inherited mutations in genes encoding factors involved in mtDNA maintenance and replication, like POLG (OMIM 174763) or PEO1 (encoding Twinkle; OMIM 606075), or in genes involved in mitochondrial nucleotide metabolism, like SLC25A4 (encoding ANT1, the Adenine Nucleotide Translocator; OMIM 103220). Clinical presentations include the multisystem Kearns-Sayre syndrome (KSS; OMIM 530000), chronic progressive external ophthalmoplegia (CPEO) in its autosomal dominant or recessive forms (depending on the genetic cause) and Pearson’s syndrome (OMIM 557000). KSS patients often show progressive heart block and although cardiomyopathy is unusual, the dilated form, which leads to heart failure, has occasionally been reported.⁷

mtDNA depletion associated with cardiomyopathy
A reduction of the normal mtDNA copy number can cause a heterogeneous group of severe infantile disorders called mitochondrial DNA depletion syndromes (MDS), which have different clinical presentations including the hepatocerebral, myopathic and encephalomyopathic forms.⁴² Nevertheless, some cases of hypertrophic cardiomyopathy associated with mtDNA depletion have been described.^10,43

CARDIOPATHIES DUE TO MUTATIONS IN THE nDNA
A substantial number of mitochondrial disorders due to mutations in nuclearly encoded genes whose products are proteins with function in mitochondria have been recently characterised.6 These proteins can be classified depending on their function,4 namely: 1) structural subunits of the OXPHOS complexes; 2) proteins involved in the assembly of the complexes; 3) proteins involved in mtDNA maintenance and whose defects are responsible for the deletion and depletion syndromes (see above); 4) proteins involved in mitochondrial protein synthesis; 5) biosynthetic enzymes for lipids and cofactors; 6) proteins involved in mitochondrial remodelling (i.e., fusion and fission) and 7) proteins involved in mitochondrial biogenesis.

Mutations in nuclear-encoded structural subunits associated with cardiomyopathy
Mutations in Complex I subunits: CI is the largest and most complicated of the respiratory chain enzymes (Figure); it is made up of 45 subunits, 38 of which are nuclearly encoded. Mutations in 10 of these subunits have been described as a cause of disease. The usual clinical presentations are early-onset progressive neurological disorders characterised by infantile encephalopathy and lactic acidosis, Leigh syndrome or progressive encephalomyopathy.5 However, recessive mutations in two CI subunits, NDUFS2 (OMIM 602985) and NDUFV2 (OMIM 600532), are the cause of neonatal cardiomyopathy with lactic acidosis and early-onset progressive cardiomyopathy.^44-45
Mutations in Complex II subunits: Succinate dehydrogenase (SDH) or CII is composed of only four nuclearly encoded subunits. Mutations in the largest subunit, SDHA (OMIM 600857), had only been associated with Leigh syndrome until very recently. A report by Levitas et al. showed the association of a mutation in the SDHA gene with recessive neonatal isolated dilated cardiomyopathy in 15 patients of two large consanguineous Bedouin families.⁴⁶

Mutations in assembly factors associated with cardiomyopathy
Mutations in Complex IV assembly factors: Most of the nuclear gene defects associated with CIV deficiency are in non-structural proteins, and three of them are involved in the development of cardiomyopathy. SCO2 (OMIM 604272) is a metallochaperone involved in copper delivery to the CIV catalytic centre. The usual clinical presentation for the most frequent mutations in the SCO2 gene is early-onset, fatal hypertrophic cardiomyopathy and encephalopathy.⁴⁷ COX10 and COX15 are two enzymes involved in the biosynthesis of heme A, a necessary cofactor for CIV function. Most mutations in COX10 (OMIM 602125) cause encephalomyopathy, but severe biventricular hypertrophic cardiomyopathy is among the other clinical manifestations that have been associated with defects in this gene.48 Mutations in COX15 (OMIM 603646) can cause either Leigh syndrome or fatal infantile hypertrophic cardiomyopathy.⁴⁹
Mutations in Complex V assembly factors: Mutations in a gene encoding a protein necessary for CV biogenesis, TMEM70 (OMIM 612418), have been related to neonatal mitochondrial encephalocardiomyopathy due to ATP synthase deficiency.⁵⁰

Mutations in biosynthetic enzymes for lipids and cofactors associated with cardiomyopathy
Mutations in the Tafazzin (TAZ or G4.5, OMIM 300394) gene are the cause of defective cardiolipin synthesis. Cardiolipin is a very important lipid that is present in the mitochondrial inner membrane and is necessary for the correct function of the respiratory chain.⁵¹ The clinical presentation of TAZ defects is Barth syndrome (OMIM 302060), which is an X-linked mitochondrial myopathy, progressive hypertrophic or dilated cardiopathy with left ventricular hypertrabeculation, neutropenia, short stature and 3-methylglutaconic aciduria. Most patients die of heart failure.⁵
Friedreich ataxia (OMIM 229300) is due to a deficiency of Frataxin (FRX; OMIM 606829), an iron chaperone involved in iron-sulphur biogenesis and heme biosynthesis, which are necessary for function of the OXPHOS system . Hypertrophic cardiomyopathy is a typical feature of Friedrich ataxia.⁵

Mutations in mitochondrial remodelling proteins associated with cardiomyopathy
A dominant mutation in the gene encoding the mitochondrial fission protein dynamin-1-like (Dmn1l) has been found to be associated with a dilated cardiomyopathy phenotype with impaired OXPHOS in mice.⁵² Although mutations in the homologous gene in humans have not been shown to be linked to heart failure, DMN1L seems a good candidate for screening in cases of familial dilated cardiomyopathy.

FINAL REMARKS
Cardiomyopathy is the most common non-neurological presentation in mitochondrial disorders, which is not surprising due to the dependence of cardiomyocytes on OXPHOS as their main energy supply. It is possible that heart dysfunction is overshadowed by the other systemic signs and that in some cases it remains unreported. However, in the literature, there is the description of a pure, nonsyndromic form of hypertrophic cardiomyopathy due to a homoplasmic point mutation in MT-TI.
The loose genotype-phenotype correlation between mitochondrial disorders and the tissue specificity, for example why mutations in the same gene sometimes affect the heart and sometimes do not, are factors of OXPHOS diseases that remain to be elucidated and an interesting research field.