Antibodies Against the ADP/ATP Carrier Interact with the Calcium Channel and Induce Cytotoxicity by Enhancement of Calcium Permeability

Abstract

Current concepts of autoimmunity emphasize the role of antibodies in the development and maintenance of autoimmune disorders. Recently we showed that the sera of patients with dilated cardiomyopathy — a suspected virus-induced autoimmune disease — contain circulating autoantibodies directed against the ADP/ATP carrier [1, 2]. The adenine nucleotide translocator is an intrinsic hydrophobic protein located in the inner mitochondrial membrane. The protein has a relative molecular weight of around 30000 and exists in the native form as a dimer [3]. Since the inner mitochondrial membrane is a priori impermeant to hydrophilic metabolites, the transfer of ATP to the cytosol with its energy-consuming processes and the return of ADP to the inner mitochondrial space for regeneration by oxidative phosphorylation requires a particular transport catalysis. The ADP/ATP shuttle, the only active nucleotide transport system in mitochondria, is highly specific and corresponds exactly to the requirements of the A TP production in aerobic cells [4]. In this study we investigated the effects of the antibodies against the ADP/ATP carrier on isolated adult rat myocytes. Immunobinding and immunofluorescence studies showed a specific binding of the antibodies to a cell-surface protein. Exposure of the myocytes to the antibodies resulted in enhanced calcium current and cell damage, which was prevented by the addition of calcium-channel blockers. These studies provide evidence for an interaction of the anti-ADP/ATP carrier antibodies with the calcium channel and suggest a new mechanism for cytotoxicity.