Adeno-associated virus-mediated gene transfer of the heart/muscle adenine nucleotide translocator (ANT) in mouse

Flierl, Adrian; Y, Chen,; Coşkun, Pınar; Samulski, R. Jude; Wallace, Douglas C.

doi:10.1038/sj.gt.3302443

Cited by 52 publications

(43 citation statements)

References 46 publications

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“…This raises the mitochondrial ratio of NADH to NAD + , inhibiting the tricarboxylic acid cycle, and resulting in the accumulation of pyruvate and NADH in cytosol that drives lactic acidosis (12,38). The high electron density of the respiratory chain enzymes also increases single electron transfer to O 2 , resulting in elevated mitochondrial ROS production (1,13,36,39,40).…”

Section: (B and C)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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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: (B and C)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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“…Although recent studies have demonstrated that ANT may not be essential for MPTP formation (20), cyclophilin D-deficient mice provide strong evidence that cyclophilin D plays a critical role not only in MPTP formation but also in the induction of necrotic cell death (2,34). Characterizing the mechanism(s) regulating ANT function and the role of the interaction between ANT and cyclophilin D may be important not only in the elucidation of pathways contributing to necrosis but also in understanding the pathogenesis of various diseases such as breast, ovarian, and uterine cancers (40), viral cardiomyopathy (41), and certain myopathies (12) which may result from the altered expression or function of either ANT or cyclophilin D.…”

mentioning

confidence: 99%

Inhibition of ADP/ATP Exchange in Receptor-Interacting Protein-Mediated Necrosis

Temkin¹,

Huang²,

Liu³

et al. 2006

Molecular and Cellular Biology

188

136

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Receptor-interacting protein (RIP) has been implicated in the induction of death receptor-mediated, nonapoptotic cell death. However, the mechanisms remain to be elucidated. Here we show that tumor necrosis factor alpha induced RIP-dependent inhibition of adenine nucleotide translocase (ANT)-conducted transport of ADP into mitochondria, which resulted in reduced ATP and necrotic cell death. The inhibition of ADP/ATP exchange coincided with the loss of interaction between ANT and cyclophilin D and the inability of ANT to adopt the cytosolic conformational state, which prevented cytochrome c release. Neither overexpression of Bcl-x L nor inhibition of reactive oxygen species prevented necrosis. In contrast, the ectopic expression of ANT or cyclophilin D was effective at preventing cell death. These observations demonstrate a novel mechanism initiated through death receptor ligation and mediated by RIP that results in the suppression of ANT activity and necrosis.Receptor Interacting Protein 1 (RIP) is essential for both tumor necrosis factor alpha (TNF-␣)-and Fas-mediated 21), which may protect against apoptotic cell death by the expression of survival genes such as FLIP (36). However, in certain cell types, when caspase activation is prevented, even when NF-B activation is not suppressed, the ligation of TNFR1 or Fas results in necrotic cell death by a mechanism that involves RIP (16,25). Although reactive oxygen species (ROS) have been implicated (25), the mechanism(s) by which RIP may mediate necrotic cell death remains to be elucidated. Characterizing the mechanisms which regulate this process is important, since necrosis is observed in a variety of pathogenic infections, ischemia, and inflammatory conditions (38) and since caspase inhibition resulted in TNF-␣-induced shock (6). This understanding is particularly important for monocytic cells and macrophages, which express both Fas and Fas ligand (36) and produce abundant TNF-␣.Modulation of the life-supporting functions of mitochondria, such as maintaining internal homeostasis and ATP synthesis, may be involved in regulation of caspase-dependent and caspase-independent cell death (13, 17, 35). Mitochondrial synthesis of ATP requires ADP transport from cytosol into mitochondria by the inner mitochondrial membrane ADP/ ATP carrier adenine nucleotide translocase (ANT) (11). ADP/ ATP exchange depends on transition between two conformational states of ANT. In the cytosolic state (c-state) the hydrophilic loop of the ANT nucleotide binding site faces the cytosol, while in the m-state, this binding site faces the matrix (11,30). Additionally, ANT function may depend on other mitochondrial molecules, including VDAC, hexokinase, and cyclophilin D (47). The interaction of ANT with cyclophilin D and VDAC is important in regulating mitochondrial permeability transition pore (MPTP). Although recent studies have demonstrated that ANT may not be essential for MPTP formation (20), cyclophilin D-deficient mice provide strong evidence that cyclophilin D plays a critical role no...

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“…The rAAV-ANT1 vector was used to transduce ANT1 activity into the skeletal muscle of ANT1-deficient mice. The transgene ANT1 protein was targeted to the mitochondrion, was inserted into the mitochondrial inner membrane, formed a functional ADP/ ATP carrier, increased the mitochondrial export of ATP and reversed the histopathological changes associated with the mitochondrial myopathy [Flierl et al, 2005]. However, ANT1 expression could only be observed in close vicinity of the injection site.…”

Section: Raav Mediated Gene Transfermentioning

confidence: 99%

Emerging therapeutic approaches to mitochondrial diseases

Wenz

Williams

Bacman

et al. 2010

Dev Disabil Res Revs

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Mitochondrial diseases are very heterogeneous and can affect different tissues and organs. Moreover, they can be caused by genetic defects in either nuclear or mitochondrial DNA as well as by environmental factors. All of these factors have made the development of therapies difficult. In this review article, we will discuss emerging approaches to the therapy of mitochondrial disorders, some of which are targeted to specific conditions whereas others may be applicable to a more diverse group of patients.

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Adeno-associated virus-mediated gene transfer of the heart/muscle adenine nucleotide translocator (ANT) in mouse

Cited by 52 publications

References 46 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

Inhibition of ADP/ATP Exchange in Receptor-Interacting Protein-Mediated Necrosis

Emerging therapeutic approaches to mitochondrial diseases

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