Differential expression of adenine nucleotide translocator isoforms in mammalian tissues and during muscle cell differentiation.

Stepien, Georges; Torroni, Antonio; Chung, Andrew B.; Hodge, J A; Wallace, Douglas C.

doi:10.1016/s0021-9258(18)42082-0

Cited by 288 publications

(55 citation statements)

References 46 publications

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“…The fact that all species tested to date, from yeast to mammals, have several ANT isoforms with specific regulated expression and tissue-specific expression patterns [6][7][8] strongly suggests specific roles and/or properties of the different isoforms. Several lines of evidence support this conclusion.…”

Section: Discussionmentioning

confidence: 99%

“…liver) and in proliferating cells (e.g. embryonic, blood cells and cancer cells) [6][7][8]10] characterized by low OXPHOS activity and high glycolysis, even in the presence of oxygen (Warburg effect) [37]. This expression pattern points to a special role for this isoform in the context of OXPHOS.…”

Section: Discussionmentioning

confidence: 99%

“…Several genes encode ANT isoforms in the vast majority of organisms, from yeast to humans. In humans, there are four ANT isoforms that exhibit cell-and tissue-specific expression [6][7][8]. Human ANT1 (hANT1) is prominently expressed in highly oxidative cells of muscle lineage, such as skeletal muscle and heart, but is also expressed in other highly oxidative tissues, such as the brain.…”

Section: Introductionmentioning

confidence: 99%

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Changes in the expression of the human adenine nucleotide translocase isoforms condition cellular metabolic/proliferative status

2016

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Human cells express four mitochondrial adenine nucleotide translocase (hANT) isoforms that are tissue-specific and developmentally regulated. hANT1 is mainly expressed in terminally differentiated muscle cells; hANT2 is growthregulated and is upregulated in highly glycolytic and proliferative cells; and hANT3 is considered to be ubiquitous and non-specifically regulated. Here, we studied how the expression of hANT isoforms is regulated by proliferation and in response to metabolic stimuli, and examined the metabolic consequences of their silencing and overexpression. In HeLa and HepG2 cells, expression of hANT3 was upregulated by shifting metabolism towards oxidation or by slowed growth associated with contact inhibition or growth-factor deprivation, indicating that hANT3 expression is highly regulated. Under these conditions, changes in hANT2 mRNA expression were not observed in either HeLa or HepG2 cells, whereas in SGBS preadipocytes (which, unlike HeLa and HepG2 cells, are growth-arrest-sensitive cells), hANT2 mRNA levels decreased. Additionally, overexpression of hANT2 promoted cell growth and glycolysis, whereas silencing of hANT3 decreased cellular ATP levels, limited cell growth and induced a stress-like response. Thus, cancer cells require both hANT2 and hANT3, depending on their proliferation status: hANT2 when proliferation rates are high, and hANT3 when proliferation slows.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Changes in the expression of the human adenine nucleotide translocase isoforms condition cellular metabolic/proliferative status

2016

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“…Myotubes, which are multinucleated post-mitotic muscle cells, naturally express high levels of ANT1 (19); thus, we reasoned that transduction of ANT1 in these cells would not cause the apoptotic cell death observed in proliferating cultured cells (18). Therefore, we used an immortalized line of mouse myoblasts, C2C12 cells, which can be efficiently differentiated into myotubes using low-serum culture conditions (20).…”

Section: Cloning and Expression Of Human Ant1 In C2c12 Mouse Myotubesmentioning

confidence: 99%

adPEO mutations in ANT1 impair ADP-ATP translocation in muscle mitochondria

Kawamata

Tiranti²,

Magrané

et al. 2011

Human Molecular Genetics

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Mutations in the heart and muscle isoform of adenine nucleotide translocator 1 (ANT1) are associated with autosomal-dominant progressive external opthalmoplegia (adPEO) clinically characterized by exercise intolerance, ptosis and muscle weakness. The pathogenic mechanisms underlying the mitochondrial myopathy caused by ANT1 mutations remain largely unknown. In yeast, expression of ANT1 carrying mutations corresponding to the human adPEO ones causes a wide range of mitochondrial abnormalities. However, functional studies of ANT1 mutations in mammalian cells are lacking, because they have been hindered by the fact that ANT1 expression leads to apoptotic cell death in commonly utilized replicating cell lines. Here, we successfully express functional ANT1 in differentiated mouse myotubes, which naturally contain high levels of ANT1, without causing cell death. We demonstrate, for the first time in these disease-relevant mammalian cells, that mutant human ANT1 causes dominant mitochondrial defects characterized by decreased ADP-ATP exchange function and abnormal translocator reversal potential. These abnormalities are not due to ANT1 loss of function, because knocking down Ant1 in myotubes causes functional changes different from ANT1 mutants. Under certain physiological conditions, mitochondria consume ATP to maintain membrane potential by reversing the ADP-ATP transport. The modified properties of mutant ANT1 can be responsible for disease pathogenesis in adPEO, because exchange reversal occurring at higher than normal membrane potential can cause excessive energy depletion and nucleotide imbalance in ANT1 mutant muscle cells.

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“…SLC25A4 (ANT1) encodes ADP/ATP translocase 1 and is required for the exchange of ADP from the cytoplasm with ATP generated by the mitochondria [30]. Indolent or mild PEO phenotypes, with or without ptosis, were described in 39 patients with SLC25A4 mutations.…”

Section: Slc25a4 -Adp/atp Translocasementioning

confidence: 99%

Adult-onset Mendelian PEO Associated with Mitochondrial Disease

Sommerville

Chinnery

Gorman

et al. 2014

Journal of Neuromuscular Diseases

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Background: Progressive external ophthalmoplegia (PEO) is an eye movement disorder characterised by paresis of the extra ocular muscles and muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Classification of patients is particularly difficult due to overlapping phenotypes and a poor genotype-phenotype relationship. Despite the identification of several nuclear encoded genes causing PEO, over half of patients with clinically confirmed PEO do not have a genetic diagnosis. Objective: To systematically review genotypic and phenotypic correlates of published cases of adult-onset PEO. Methods: Patients were identified from interrogation of articles from Scopus, Medline via PubMed, and Genetic Abstracts databases using electronic searches (1st January 1970 to 8th November 2013). Reference lists and UniProt entries were also manually checked for additional articles. Results: Twelve nuclear encoded genes were identified (TYMP,

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Differential expression of adenine nucleotide translocator isoforms in mammalian tissues and during muscle cell differentiation.

Cited by 288 publications

References 46 publications

Changes in the expression of the human adenine nucleotide translocase isoforms condition cellular metabolic/proliferative status

Changes in the expression of the human adenine nucleotide translocase isoforms condition cellular metabolic/proliferative status

adPEO mutations in ANT1 impair ADP-ATP translocation in muscle mitochondria

Adult-onset Mendelian PEO Associated with Mitochondrial Disease

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