Carboxyatractyloside effects on brown-fat mitochondria imply that the adenine nucleotide translocator isoforms ANT1 and ANT2 may be responsible for basal and fatty-acid-induced uncoupling respectively

Irina G. Shabalina , Tatiana V. Kramarova , Jan Nedergaard , Barbara Cannon (1)

1 The Wenner-Gren Institute

In brown-fat mitochondria, fatty acids induce thermogenic uncoupling through activation of Uncoupling Protein-1 (UCP1). However, even in brown-fat mitochondria from UCP1(-/-) mice, fatty acid-induced uncoupling exists. In the present investigation, we used the inhibitor carboxyatractyloside (CAtr) to examine the involvement of the adenine nucleotide translocator (ANT) in the mediation of this UCP1-independent fatty acid-induced uncoupling in brown-fat mitochondria. We found that the contribution of ANT to fatty acid-induced uncoupling in UCP1(-/-) brown-fat mitochondria was minimal (whereas it was responsible for nearly half the fatty acid-induced uncoupling in liver mitochondria). As compared to liver mitochondria, brown-fat mitochondria exhibit a relatively high (UCP1-independent) basal respiration ("proton leak"). Unexpectedly, a large fraction of this high basal respiration was sensitive to CAtr (whereas in liver mitochondria, basal respiration was CAtr-insensitive). Total ANT protein levels were similar in brown-fat mitochondria (from wild-type mice) and in liver mitochondria (but the level was increased in brown-fat mitochondria from UCP1(-/-) mice). However, in liver, only Ant2 mRNA was found, whereas in brown adipose tissue, Ant1 and Ant2 mRNA levels were equal. The data are therefore compatible with a tentative model in which the Ant2 isoform is the one that mediates fatty acid-induced uncoupling whereas the Ant1 isoform is the one that may mediate a significant part of the high basal proton leak in brown-fat mitochondria.

Mots clés: Life Sciences

Irina G. Shabalina, Tatiana V. Kramarova, Jan Nedergaard, Barbara Cannon. Carboxyatractyloside effects on brown-fat mitochondria imply that the adenine nucleotide translocator isoforms ANT1 and ANT2 may be responsible for basal and fatty-acid-induced uncoupling respectively. Biochemical Journal, 2006, 399 (3), pp.405-414. ⟨10.1042/BJ20060706⟩. ⟨hal-00478595⟩