ARL2 and BART Enter Mitochondria and Bind the Adenine Nucleotide Transporter

Sharer, J. Daniel; Shern, Jack F.; Valkenburgh, Hillary Van; Wallace, Douglas C.; Kahn, Richard

doi:10.1091/mbc.01-05-0245

Cited by 90 publications

(147 citation statements)

References 55 publications

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“…In separate experiments HeLa cells were stimulated with 20 ng/ml TNF␣ for 60 min before the cells were collected. For gel retardation assays, a doublestranded oligonucleotide containing a consensus NF-B DNA binding site (5Ј-TCT AGA GTT GAG GGG ACT TTC CCA G-3Ј, obtained from Roche Applied Science) was end-labeled using [␣- 32 P]dCTP and Klenow enzyme. Nuclear protein extracts (10 g) were incubated for 10 min on ice with binding buffer (25 mM Hepes, pH 7.6, 0.5 mM dithiothreitol, 12.5 mM ZnSO 4 , 50 mM KCl, 1 mg/ml bovine serum albumin, 5% glycerol, 0.1% Nonidet P-40, and 2.5 g of poly(dI-dC) (deoxyinosinic-deoxycytidylic acid)).…”

Section: Methodsmentioning

confidence: 99%

Recruitment of NF-κB into Mitochondria Is Involved in Adenine Nucleotide Translocase 1 (ANT1)-induced Apoptosis

Zamora

Meroño

Viñas³

et al. 2004

Journal of Biological Chemistry

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Overexpression of adenine nucleotide translocase-1 (ANT1) is known to induce apoptosis (Bauer, M. K., Schubert, A., Rocks, O., and Grimm, S. (1999) J. Cell Biol. 147, 1493-1501), but the mechanisms involved remain unclear. In this study we show that ANT1 overexpression results in a recruitment of the IB␣-NF-B complex into mitochondria, with a coincident decrease in nuclear NF-B DNA binding activity. In this situation, NF-B transcriptionally regulated genes with antiapoptotic activity, such as Bcl-XL, MnSOD2, and c-IAP2, are down-regulated, and consequently, cells are sensitized to apoptosis. Accordingly, co-expression of p65 partially interferes with the proapoptotic effect of ANT1 overexpression. Despite the high identity of the two isoforms, overexpression of ANT2 does not exert an apoptotic effect; this lack of apoptotic activity is correlated with the absence of mitochondrial IB␣-NF-B recruitment or changes in NF-B activity. Thus, we propose that the mitochondrial recruitment of NF-B observed following ANT1 overexpression has an important role in ANT1 proapoptotic activity.Apoptosis is a form of cell death that plays a role in development, tissue homeostasis, and disease (1). The induction of apoptosis is governed by an elaborate array of checks and balances in the cell. Studies of apoptosis induction in "in vitro" systems have demonstrated that mitochondria are required for the apoptosis stimulated by a variety of different factors (2).The ANT 1 protein is localized in the inner mitochondrial membrane and exchanges cytosolic ADP for mitochondrial ATP (3). Three isoforms (ANT1, ANT2, and ANT3) with tissuespecific expression patterns have been described in humans (4). ANT interacts with several proteins of the outer mitochondrial membrane (peripheral benzodiazepine receptor, porin/VDAC, and Bax) as well as the matrix (cyclophilin D) to form the permeability transition pore (PTP) (5). The PTP appears to be an important regulator of the apoptotic process. Opening of the pore leads to a loss of mitochondrial transmembrane potential, ⌬⌿ m , which can ultimately culminate in matrix swelling and outer membrane rupture, allowing the release of apoptogenic proteins such as cytochrome c, apoptosis-inducing factor, and procaspases (6, 7). Proteins of the bcl-2 family essentially control the release of cytochrome c. Antiapoptotic members of the family (Bcl-2 and Bcl-XL) prevent cytochrome release, whereas the proapoptotic members Bax and Bak exert the opposite effect (8). Bax has been shown to interact with ANT to induce PTP opening and cytochrome c release (9). Several pharmacological compounds interfere with PTP. For instance, cyclosporin A, through its binding to cyclophilin D, prevents PTP opening, and bongkrekic acid and atractyloside are, respectively, a blocker and an inducer of apoptosis via binding of two different conformational states of ANT (10). In addition, alongside their modulation of pore formation by ANT, Bcl-2 and Bax also have been reported to influence ANT ADP/ATP antiporter activity (11). Although ...

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Section: Methodsmentioning

confidence: 99%

Recruitment of NF-κB into Mitochondria Is Involved in Adenine Nucleotide Translocase 1 (ANT1)-induced Apoptosis

Zamora

Meroño

Viñas³

et al. 2004

Journal of Biological Chemistry

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“…ANT1 is the predominant isoform expressed in the mitochondria of heart and skeletal muscle tissue. In addition to regulating adenine nucleotide pools, ANT1 functions as a component of the mitochondrial permeability transition pore (PTP), which is essential for the release of pro-apoptotic proteins during the activation of the intrinsic-apoptosis pathway (Bauer et al, 1999;Sharer et al, 2002). ANT1 overexpression seems critical in inducing programmed cell death in different eukaryotic cell lines (Bauer et al, 1999).…”

Section: Adenine Nucleotide Translocator (Ant1)mentioning

confidence: 99%

Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

Salani¹,

Morini²,

Scionti³

et al. 2012

Neuromuscular Disorders

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“…7 There has been no clear experimental evidence to date that differential ATP transport kinetics among the paralogs are critical for their specific roles in cells or tissues. Besides ATP transport activity, multiple studies indicate ANT paralogs may differ in their intramitochondrial sublocalization, 8 uncoupling activities, 9 binding partners 10 and effects on mitochondrial permeability transition pore (mPTP) opening and subsequent cellular survival and death control. 11 These intriguing subjects, however, have not been confirmed rigorously after the initial reports.…”

mentioning

confidence: 99%

Mitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis

Seo

et al. 2015

Cell Death Differ

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Adenine nucleotide translocases (ANTs) transport ADP and ATP through mitochondrial inner membrane, thus playing an essential role for energy metabolism of eukaryotic cells. Mice have three ANT paralogs, Ant1 (Slc25a4), Ant2 (Slc25a5) and Ant4 (Slc25a31), which are expressed in a tissue-dependent manner. While knockout mice have been characterized with Ant1 and Ant4 genes, which resulted in exercise intolerance and male infertility, respectively, the role of the ubiquitously expressed Ant2 gene in animal development has not been fully demonstrated. Here, we generated Ant2 hypomorphic mice by targeted disruption of the gene, in which Ant2 expression is largely depleted. The mice showed apparently normal embryonic development except pale phenotype along with a reduced birth rate. However, postnatal growth was severely retarded with macrocytic anemia, B lymphocytopenia, lactic acidosis and bloated stomach, and died within 4 weeks. Ant2 depletion caused anemia in a cell-autonomous manner by maturation arrest of erythroid precursors with increased reactive oxygen species and premature deaths. B-lymphocyte development was similarly affected by Ant2 depletion, and splenocytes showed a reduction in maximal respiration capacity and cellular ATP levels as well as an increase in cell death accompanying mitochondrial permeability transition pore opening. In contrast, myeloid, megakaryocyte and T-lymphocyte lineages remained apparently intact. Erythroid and B-cell development may be particularly vulnerable to Ant2 depletion-mediated mitochondrial dysfunction and oxidative stress.

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ARL2 and BART Enter Mitochondria and Bind the Adenine Nucleotide Transporter

Cited by 90 publications

References 55 publications

Recruitment of NF-κB into Mitochondria Is Involved in Adenine Nucleotide Translocase 1 (ANT1)-induced Apoptosis

Recruitment of NF-κB into Mitochondria Is Involved in Adenine Nucleotide Translocase 1 (ANT1)-induced Apoptosis

Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

Mitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis

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