期刊
CELL DEATH AND DIFFERENTIATION
卷 16, 期 11, 页码 1480-1492出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2009.100
关键词
adenine nucleotide translocator; mitochondria; transglutaminase
资金
- Associazione Italiana Ricerca sul Cancro [GGP06254]
- Ministero della Sanita [LSHM-CT-2004-503116]
- MRC [MC_U132670600] Funding Source: UKRI
- Medical Research Council [MC_U132670600] Funding Source: researchfish
- Fondazione Telethon Funding Source: Custom
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. Cell Death and Differentiation (2009) 16, 1480-1492; doi: 10.1038/cdd.2009.100; published online 31 July 2009
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