Complete loss of expression of the<i>ANT1</i>gene causing cardiomyopathy and myopathy

Echaniz‐Laguna, Andoni; Chassagne, Maïté; Ceresuela, Jennifer; Rouvet, Isabelle; Padet, Sylvie; Acquaviva, Cécile; Nataf, Serge; Vinzio, S.; Bozon, Dominique; Camaret, Bénédicte Mousson de

doi:10.1136/jmedgenet-2011-100504

Cited by 66 publications

(55 citation statements)

References 20 publications

(21 reference statements)

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“…Clinical analysis of nine related ANT1 −/− patients has confirmed that complete absence of ANT1 activity in humans is associated with lactic academia, cardiomyopathy, and mitochondrial myopathy without CPEO, consistent with previous case reports (5,6). Therefore, ANT1…”

Section: Discussionsupporting

confidence: 88%

“…Mutations in a number of nuclear DNA (nDNA)-encoded mitochondrial proteins impair OXPHOS and cause cardiomyopathy (4). Recently, two case reports demonstrated homozygous solute carrier family 25, member 4 (SCL25A4) (adenine nucleotide translocator-1, ANT1) mutations (A123D; c.111+1G > A) (5,6) in patients who had cardiomyopathy and mitochondrial myopathy without the chronic progressive external ophthalmoplegia (CPEO) characteristic of certain autosomal dominant ANT1 missense mutations (L98P, A90D, D104G, A114P, and V289M) (7)(8)(9)(10).…”

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confidence: 99%

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Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup

Strauss

DuBiner

Simon

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Mutations of both nuclear and mitochondrial DNA (mtDNA)-encoded mitochondrial proteins can cause cardiomyopathy associated with mitochondrial dysfunction. Hence, the cardiac phenotype of nuclear DNA mitochondrial mutations might be modulated by mtDNA variation. We studied a 13-generation Mennonite pedigree with autosomal recessive myopathy and cardiomyopathy due to an SLC25A4 frameshift null mutation (c.523delC, p.Q175RfsX38), which codes for the heart-muscle isoform of the adenine nucleotide translocator-1. Ten homozygous null (adenine nucleotide translocator-1) patients monitored over a median of 6 years had a phenotype of progressive myocardial thickening, hyperalaninemia, lactic acidosis, exercise intolerance, and persistent adrenergic activation. Electrocardiography and echocardiography with velocity vector imaging revealed abnormal contractile mechanics, myocardial repolarization abnormalities, and impaired left ventricular relaxation. End-stage heart disease was characterized by massive, symmetric, concentric cardiac hypertrophy; widespread cardiomyocyte degeneration; overabundant and structurally abnormal mitochondria; extensive subendocardial interstitial fibrosis; and marked hypertrophy of arteriolar smooth muscle. Substantial variability in the progression and severity of heart disease segregated with maternal lineage, and sequencing of mtDNA from five maternal lineages revealed two major European haplogroups, U and H. Patients with the haplogroup U mtDNAs had more rapid and severe cardiomyopathy than those with haplogroup H. ANT1 | oxidative stress | mitochondrial disease | variable penetrance | oxidative phosphorylation

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Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup

Strauss

DuBiner

Simon

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Similarly, PC level was shown to correlate with NYHA classification and high plasma levels of PC were significantly associated with serious adverse events and poor prognostic of heart failure patients [64]. Finally, decreased ANT function per se triggers a progressive cardiomyopathy and elicits arrhythmic events [15,[65][66][67] associated with mitochondrial ROS production [65,68].…”

Section: Discussionmentioning

confidence: 96%

Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase

Roussel

Thireau

Brenner

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Long chain fatty acids bind to carnitine and form long chain acyl carnitine (LCAC), to enter into the mitochondria. They are oxidized in the mitochondrial matrix. LCAC accumulates rapidly under metabolic disorders, such as acute cardiac ischemia, chronic heart failure or diabetic cardiomyopathy. LCAC accumulation is associated with severe cardiac arrhythmia including ventricular tachycardia or fibrillation. We thus hypothesized that palmitoyl-carnitine (PC), alters mitochondrial function leading to Ca(2+) dependent-arrhythmia. In isolated cardiac mitochondria from C57Bl/6 mice, application of 10μM PC decreased adenine nucleotide translocase (ANT) activity without affecting mitochondrial permeability transition pore (mPTP) opening. Mitochondrial reactive oxygen species (ROS) production, measured with MitoSOX Red dye in isolated ventricular cardiomyocytes, increased significantly under PC application. Inhibition of ANT by bongkrekic acid (20 μM) prevented PC-induced mitochondrial ROS production. In addition, PC increased type 2 ryanodine receptor (RyR2) oxidation, S-nitrosylation and dissociation of FKBP12.6 from RyR2, and therefore increased sarcoplasmic reticulum (SR) Ca(2+) leak. ANT inhibition or anti-oxidant strategy (N-acetylcysteine) prevented SR Ca(2+) leak, FKBP12.6 depletion and RyR2 oxidation/S-nitrosylation induced by PC. Finally, both bongkrekic acid and NAC significantly reduced spontaneous Ca(2+) wave occurrences under PC. Altogether, these results suggest that an elevation of PC disturbs ANT activity and alters Ca(2+) handling in a ROS-dependent pathway, demonstrating a new pathway whereby altered FA metabolism may contribute to the development of ventricular arrhythmia in pathophysiological conditions.

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“…A similar phenomenon has been described for human mitochondria, which also contain three isoforms of the adenine nucleotide translocase (ANT) (73). While the loss of the main ANT1 isoform is not lethal, it does induce mt myopathy, as the lack of ADP/ATP exchange activity depletes matrix ADP, which causes F o F 1 -ATP synthase stagnation (74,75). Consequently, the flow of protons back to the matrix is blocked and the ⌬m increases until it reaches a level that prohibits oxidative phosphorylation, resulting in increased ROS production and mt DNA damage (76).…”

Section: Discussionmentioning

confidence: 99%

The ADP/ATP Carrier and Its Relationship to Oxidative Phosphorylation in Ancestral Protist Trypanosoma brucei

et al. 2015

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The highly conserved ADP/ATP carrier (AAC) is a key energetic link between the mitochondrial (mt) and cytosolic compartments of all aerobic eukaryotic cells, as it exchanges the ATP generated inside the organelle for the cytosolic ADP. Trypanosoma brucei, a parasitic protist of medical and veterinary importance, possesses a single functional AAC protein (TbAAC) that is related to the human and yeast ADP/ATP carriers. However, unlike previous studies performed with these model organisms, this study showed that TbAAC is most likely not a stable component of either the respiratory supercomplex III؉IV or the ATP synthasome but rather functions as a physically separate entity in this highly diverged eukaryote. Therefore, TbAAC RNA interference (RNAi) ablation in the insect stage of T. brucei does not impair the activity or arrangement of the respiratory chain complexes. Nevertheless, RNAi silencing of TbAAC caused a severe growth defect that coincides with a significant reduction of mt ATP synthesis by both substrate and oxidative phosphorylation. Furthermore, TbAAC downregulation resulted in a decreased level of cytosolic ATP, a higher mt membrane potential, an elevated amount of reactive oxygen species, and a reduced consumption of oxygen in the mitochondria. Interestingly, while TbAAC has previously been demonstrated to serve as the sole ADP/ATP carrier for ADP influx into the mitochondria, our data suggest that a second carrier for ATP influx may be present and active in the T. brucei mitochondrion. Overall, this study provides more insight into the delicate balance of the functional relationship between TbAAC and the oxidative phosphorylation (OXPHOS) pathway in an early diverged eukaryote. The origination event of an ADP/ATP carrier (AAC) was crucial in the evolution of the present-day mitochondrion that enabled it to become the powerhouse of the eukaryotic cell. Due to the activity of AAC, the energy-producing mitochondria can supply the cytosol with ATP molecules, which fuel most cellular reactions. AAC belongs to the well-defined family of mitochondrial (mt) carrier proteins that are located in the inner mt membrane and are involved in the transport of a wide range of metabolites (1). Under physiological aerobic conditions, AAC is responsible for the 1:1 counterexchange of mt ATP for cytosolic ADP (2). mt ATP is produced mainly by the evolutionarily conserved biochemical pathway of oxidative phosphorylation (OXPHOS), which employs respiratory complexes I through IV to convert the redox energy of various mt substrates into an electrochemical proton gradient (⌬m) across the mt inner membrane. Respiratory complexes I (NADH-ubiquinone oxidoreductase) and II (succinate-ubiquinone oxidoreductase) are responsible for the oxidation of reduced NADH and FADH 2 , respectively. The electrons derived from these biochemical processes continue along the electron transport chain as they are sequentially passed to coenzyme Q, complex III (ubiquinol-cytochrome c oxidoreductase), cytochrome c, complex IV (cytochrome c-O 2 oxid...

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Complete loss of expression of theANT1gene causing cardiomyopathy and myopathy

Cited by 66 publications

References 20 publications

Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup

Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup

Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase

The ADP/ATP Carrier and Its Relationship to Oxidative Phosphorylation in Ancestral Protist Trypanosoma brucei

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