Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2+

Nickolay Brustovetsky, Martin Klingenberg

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371 Scopus citations


Single-channel current measurements of excised patches with reconstituted purified mitochondrial ADP/ATP carrier (AAC) indicates the presence of a large low cation selective (P(K)+/P(Cl-) = 4.3 ± 0.6) channel. The channel conductance has multiple sublevels and varies from 300 to 600 pS. It has low probability of current fluctuations at V(hold) up to 80-100 mV of both signs and is reversibly gated at V(hold) > 150 mV. The opening of the channel is Ca2+-dependent (1 mM Ca2+) and can be reversibly closed on removal of Ca2+. It is strongly pH dependent and closes completely at pH(ex) 5.2. The AAC-specific inhibitor bongkrekate inhibits the channel partially and completely in combination with ADP, whereas carboxyatractylate did not affect the conductance. The effects of these AAC-specific ligands prove that the channel activity belongs to AAC. The AAC-linked conductance can clearly be differentiated from the porin channel, rarely detected in our preparations. The properties of the AAC- linked channel coincide with the mitochondrial permeability transition pore (MTP), which is also affected by the AAC ligands [Hunter, D. R., and Haworth, R. A. (1979) Arch. Biochem. Biophys. 195, 453-459] and resembles the mitochondrial 'multiconductance channel' [Kinnally, K. W., Campo, M. L., and Tedeschi, H. T. (1989) J. Bioenerg. Biomembr. 21, 497-506] or 'megachannel' [Petronilli, V., Szabo, I., and Zoratti, M. (1989) FEBS Lett. 259, 137-143]. Therefore we conclude that the AAC, when converted into a large unselective channel, is a key component in the MTP and thus is involved in the ischemia- reperfusion damage and cytosolic Ca2+ oscillations. The channel opening in AAC is proposed to be caused by binding of Ca2+ to the cardiolipin, tightly bound to AAC, thus releasing positive charges within the AAC which open the gate.

Original languageEnglish (US)
Pages (from-to)8483-8488
Number of pages6
Issue number26
StatePublished - Aug 1 1996
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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