Biochem. J. (2013) 453, 321–336 (Printed in Great Britain) doi:10.1042/BJ20130079 321 REVIEW ARTICLE Biochemistry of cardiomyopathy in the mitochondrial disease Friedreich’s ataxia Darius J. R. LANE 1 , Michael Li-Hsuan HUANG 1 , Samantha TING, Sutharshani SIVAGURUNATHAN and Des R. RICHARDSON 2 Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, NSW 2006, Australia FRDA (Friedreich’s ataxia) is a debilitating mitochondrial disorder leading to neural and cardiac degeneration, which is caused by a mutation in the frataxin gene that leads to decreased frataxin expression. The most common cause of death in FRDA patients is heart failure, although it is not known how the deficiency in frataxin potentiates the observed cardiomyopathy. The major proposed biochemical mechanisms for disease pathogenesis and the origins of heart failure in FRDA involve metabolic perturbations caused by decreased frataxin expression. Additionally, recent data suggest that low frataxin expression in heart muscle of conditional frataxin knockout mice activates an integrated stress response that contributes to and/or exacerbates cardiac hypertrophy and the loss of cardiomyocytes. The elucidation of these potential mechanisms will lead to a more comprehensive understanding of the pathogenesis of FRDA, and will contribute to the development of better treatments and therapeutics. Key words: apoptosis, autophagy, cardiomyopathy, frataxin, Friedreich’s ataxia, integrated stress response. INTRODUCTION FRDA (Friedreich’s ataxia) is an autosomal recessive neuro- and cardio-degenerative disorder that is caused by the deficient expression of the nuclear-encoded mitochondrial protein frataxin [1,2]. It is characterized by gait and limb ataxia, dysarthria, absent muscle stretch reflexes in the lower limbs, sensory loss and pyramidal signs [2,3]. In addition, patients generally suffer from skeletal deformities, diabetes and cardiomyopathy [2]. The disorder has an estimated prevalence of 1 in 50000 in European populations, which makes it the most common hereditary ataxia in this population grouping. In contrast, the disease is far rarer among Asians, sub-Saharan Africans and American–Indians [2,4–6]. Frataxin deficiency is primarily due to a homozygous GAA triplet repeat expansion in the first intron of the frataxin gene FXN [3,7], which is located on the proximal long arm of chromosome 9 [8] at position 9q21.11 [9]. However, a minority of FRDA patients (<4 %) are compound heterozygotes possessing point or small deletion mutations in the non-expanded allele and a GAA triplet repeat expansion in the other [10,11]. Although a normal FXN allele contains 6–36 triplets, an expanded FXN allele contains 66–1700 triplets, although in the majority of cases there are 600–900 triplets [3,7,12]. Expansions in the gene cause an abnormal conformation in the DNA, resulting in decreased transcription of the FXN gene and a subsequent reduced expression of the frataxin protein [13]. Importantly, the size of the GAA repeat has been found to positively correlate with the severity of the disease and negatively correlate with the age of onset [3]. There are a number of atypical variants of FRDA [2]: (i) late- onset FRDA, where disease progression is slower and onset occurs after 25 years of age; (ii) acadian-type FRDA, in which symptoms are less severe and cardiomyopathy rarely occurs; and (iii) FRDA with retained reflexes, in which tendon reflexes in the lower limbs are preserved and clinical features are less pronounced. These atypical variants with less severe symptoms such as late- onset FRDA typically have shorter GAA expansions [14]. The pathogenesis of the typical form of FRDA has a mean age of onset at 10.5 + − 7.4 years and death at 37.5 + − 14.4 years of age [15]. The association of FRDA with mitochondrial dysfunction is supported by a large body of evidence. The mitochondrion is not only a vital organelle for energy transduction and the regulation of cell death [16], but it is also important in iron metabolism, as it is the primary site for haem and ISC (iron–sulfur cluster) synthesis [17–20]. In fact, iron is incorporated into haem and ISCs for utilization in the cytosol for incorporation into a variety of proteins. Both the haem and ISC biosynthetic pathways are signi- ficantly affected in FRDA [17,18,21,22]. Hence, as a result of the disruption of normal mitochondrial function, some of the notable features that are observed in the disorder include mitochondrial iron accumulation in the heart and ISC deficiency [21,23–27]. In addition, FRDA primarily affects mitochondria-rich tissues, particularly those containing post-mitotic cells and those that are Abbreviations used: AMPK, AMP-activated protein kinase; Asns, asparagine synthetase; ATF4, activating transcription factor 4; Atg, autophagy-related; Bcl-2, B-cell lymphoma 2; Chop, C/EBP (CCAAT/enhancer-binding protein)-homologous protein; Ctr1, copper transporter 1; eIF, eukaryotic initiation factor; eIF2AK, eIF2α kinase; ER, endoplasmic reticulum; FRDA, Friedreich’s ataxia; Ftmt, mitochondrial ferritin; FXN, frataxin; Gcn2, general control non- derepressing 2; HIF, hypoxia-inducible factor; Hri, haem-regulated inhibitor; IRP, iron-regulatory protein; ISC, iron–sulfur cluster; ISCU, iron–sulfur cluster scaffold protein; ISR, integrated stress response; KO, knockout; LC3, microtubule-associated protein 1 light chain 3; MCK, muscle creatine kinase; MnSOD, manganese superoxide dismutase; Mthfd2 , methylenetetrahydrofolate dehydrogenase (NADP + dependent) 2; Nfs1, cysteine desulfurase; NSE, neurone- specific enolase; PERK, PKR (double-stranded-RNA-dependent protein kinase)-like endoplasmic reticulum kinase; PIX, protoporphyrin IX; Pkr, protein kinase R; Psat1, phosphoserine aminotransferase 1; TfR1, transferrin receptor 1; TNF, tumour necrosis factor; TRADD, tumour-necrosis-factor-associated death domain; Trib3 , Tribbles homologue 3. 1 These authors contributed equally to this work. 2 To whom correspondence should be addressed (email d.richardson@med.usyd.edu.au). c  The Authors Journal compilation c  2013 Biochemical Society