The mitochondrial ADP/ATP carrier: Structural, physiological and pathological aspects

Fiore, Christelle; Trezeguet, Véronique; Saux, Agnès Le; Roux, P.; Schwimmer, Christine; Dianoux, Anne-Christine; Noël, Florence; Lauquin, Guy J.‐M.; Brandolin, Gérard; Vignais, Pierre V.

doi:10.1016/s0300-9084(98)80020-5

Cited by 203 publications

(154 citation statements)

References 65 publications

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“…AAC, also known as adenine nucleotide translocase or ADP/ATP translocase, is the major ADP/ ATP transporter located on the mitochondria inner membrane, catalyzing the exchange of ATP produced in mitochondria matrix with ADP in cytosol. 25 Four AAC isoforms have been identified in human with distinct expression patterns. 26,27 According to previous reports, [28][29][30] AAC2 and AAC3 are the dominant AACs in ECs.…”

Section: Resultsmentioning

confidence: 99%

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Zhang

et al. 2014

Cell Death Differ

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Isthmin (ISM) is a secreted 60-kDa protein that potently induces endothelial cell (EC) apoptosis. It suppresses tumor growth and angiogenesis in mice when stably overexpressed in cancer cells. Although avb5 integrin serves as a low-affinity receptor for ISM, the mechanism by which ISM mediates antiangiogenesis and apoptosis in ECs remain to be fully resolved. In this work, we report the identification of cell-surface glucose-regulated protein 78 kDa (GRP78) as a high-affinity receptor for ISM (K d ¼ 8.6 nM). We demonstrated that ISM-GRP78 interaction triggers apoptosis not only in activated ECs but also in cancer cells expressing high level of cell-surface GRP78. Normal cells and benign tumor cells tend to express low level of cell-surface GRP78 and are resistant to ISM-induced apoptosis. Upon binding to GRP78, ISM is internalized into ECs through clathrin-dependent endocytosis that is essential for its proapoptotic activity. Once inside the cell, ISM co-targets with GRP78 to mitochondria where it interacts with ADP/ATP carriers on the inner membrane and blocks ATP transport from mitochondria to cytosol, thereby causing apoptosis. Hence, ISM is a novel proapoptotic ligand that targets cell-surface GRP78 to trigger apoptosis by inducing mitochondrial dysfunction. The restricted and high-level expression of cell-surface GRP78 on cancer cells and cancer ECs make them uniquely susceptible to ISM-targeted apoptosis. Indeed, systemic delivery of recombinant ISM potently suppressed subcutaneous 4T1 breast carcinoma and B16 melanoma growth in mice by eliciting apoptosis selectively in the cancer cells and cancer ECs. Together, this work reveals a novel ISM-GRP78 apoptosis pathway and demonstrates the potential of ISM as a cancer-specific and dual-targeting anticancer agent.

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Section: Resultsmentioning

confidence: 99%

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Zhang

et al. 2014

Cell Death Differ

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“…Under normal settings, ANT functions as a highly specific transporter, having two conformational states. This is exhibited by the binding of its two potent inhibitors: carboxyatractyloside, which binds at the cytosolic side of the protein and fixes it in the "c"-conformation, and bongkrekic acid, which binds at the matrix side of the protein and fixes it in the "m"-conformation [44]. In humans, there are three known isoforms of ANT, which differ in their expression level and tissue distribution [45][46][47].…”

Section: Adp/atp Translocase (Ant)mentioning

confidence: 99%

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

2007

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Mitochondria play a pivotal role in the process of apoptosis. Alterations in mitochondrial structure and function during apoptosis are regulated by proteins of the BCL-2 family, however their exact mechanism of action is largely unknown. Mitochondrial carriers and pores play an essential role in maintaining the normal function of mitochondria, and BCL-2 family members were shown to interact with several mitochondrial carriers/pores and to affect their function. This review focuses on the involvement of several of these mitochondrial carriers/pores in the regulation of the mitochondrial death pathway.

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“…18 ANT is an antiporter whose function is strictly required for ATP produced on the matrix side of IM by the F 0/1 ATP synthase to be exported to the rest to the cell. Genetic inactivation of ANT therefore results into a severe metabolic impairment.…”

Section: Introductionmentioning

confidence: 99%

Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator

et al. 2000

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Mitochondrial membrane permeabilization can be a rate limiting step of apoptotic as well as necrotic cell death. Permeabilization of the outer mitochondrial membrane (OM) and/or inner membrane (IM) is, at least in part, mediated by the permeability transition pore complex (PTPC). The PTPC is formed in the IM/OM contact site and contains the two most abundant IM and OM proteins, adenine nucleotide translocator (ANT, in the IM) and voltage-dependent anion channel (VDAC, in the OM), the matrix protein cyclophilin D, which can interact with ANT, as well as apoptosis-regulatory proteins from the Bax/Bcl-2 family. Here we discuss that ANT has two opposite functions. On the one hand, ANT is a vital, specific antiporter which accounts for the exchange of ATP and ADP on IM. On the other hand, ANT can form a non-specific pore, as this has been shown by electrophysiological characterization of purified ANT reconstituted into synthetic lipid bilayers or by measuring the permeabilization of proteoliposomes containing ANT. Pore formation by ANT is induced by a variety of different agents (e.g. Ca 2+ , atractyloside, thiol oxidation, the pro-apoptotic HIV-1 protein Vpr, etc.) and is enhanced by Bax and inhibited by Bcl-2, as well as by ADP. In isolated mitochondria, pore formation by ANT leads to an increase in IM permeability to solutes up to 1500 Da, swelling of the mitochondrial matrix, and OM permeabilization, presumably due to physical rupture of OM. Although alternative mechanisms of mitochondrial membrane permeabilization may exist, ANT emerges as a major player in the regulation of cell death.

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The mitochondrial ADP/ATP carrier: Structural, physiological and pathological aspects

Cited by 203 publications

References 65 publications

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator

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