The adenine nucleotide translocator 1 acts as a type 2 transglutaminase substrate: Implications for mitochondrial-dependent apoptosis

W. Malorni, M. G. Farrace, P. Matarrese, A. Tinari, L. Ciarlo, P. Mousavi-Shafaei, M. D'Eletto, G. Di Giacomo, G. Melino, L. Palmieri, C. Rodolfo, M. Piacentini

Research output: Contribution to journalArticle

Abstract

In this study we provide in vitro and in vivo evidence showing that the protein disulphide isomerase (PDI) activity of type 2 transglutaminase (TG2) regulates the correct assembly and function of the mitochondrial ADP/ATP transporter adenine nucleotide translocator 1 (ANT1). We demonstrate, by means of biochemical and morphological analyses, that ANT1 and TG2 physically interact in the mitochondria. Under physiological conditions, TG2's PDI activity regulates the ADP/ATP transporter function by controlling the oligomerization of ANT1. In fact, mitochondria isolated from hearts of TG2-/- mice exhibit increased polymerization of ANT1, paralleled by an enhanced ADP/ATP carrier activity, as compared to mitochondria belonging to TG2+/+ mice. Interestingly, upon cell-death induction, ANT1 becomes a substrate for TG2's cross-linking activity and the lack of TG2 results in a reduction of apoptosis as well as in a marked sensitivity to the ADP/ATP exchange inhibition by atractyloside. These findings suggest a complex TG2-dependent regulation of the ADP/ATP transporter and reveal new important avenues for its potential applications in the treatment of some mitochondrial-dependent diseases, including cardiovascular and neurodegenerative diseases.

Original languageEnglish
Pages (from-to)1480-1492
Number of pages13
JournalCell Death and Differentiation
Volume16
Issue number11
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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    Malorni, W., Farrace, M. G., Matarrese, P., Tinari, A., Ciarlo, L., Mousavi-Shafaei, P., D'Eletto, M., Di Giacomo, G., Melino, G., Palmieri, L., Rodolfo, C., & Piacentini, M. (2009). The adenine nucleotide translocator 1 acts as a type 2 transglutaminase substrate: Implications for mitochondrial-dependent apoptosis. Cell Death and Differentiation, 16(11), 1480-1492. https://doi.org/10.1038/cdd.2009.100