Wrutniak-Cabello Chantal, Carazo Angel, Casas François, Cabello Gérard
UMR 866 Différenciation cellulaire et croissance, INRA, Université Montpellier 2, Université Montpellier 1, INRA-Supagro, 2 place Pierre Viala, 34060 Montpellier Cedex 1, France.
J Soc Biol. 2008;202(2):83-92. doi: 10.1051/jbio:2008010. Epub 2008 Jun 13.
Thyroid hormone exerts a diversity of physiological influences over developmental and metabolic processes. Searching for receptors able to mediate this extended regulation led to the identification of triiodothyronine (T3) nuclear receptors encoded by two different genes, c-erbA alpha (TR alpha) and c-erbA beta (TR beta). More recently, two N-terminally truncated forms of the triiodothyronine nuclear receptor TR alpha 1, with molecular weights of 43 and 28 kDa, have been discovered in mitochondria. Synthesized through the use of internal initiation sites of translation occurring in the TR alpha 1 transcript, they are addressed into mitochondria according to an atypical process. Two mitochondrial import sequences have been characterized in the C-terminal part of these proteins; in addition, their N-terminal part, devoid of negative charges, plays a permissive role in this import. Whereas the function of p28 remains unknown, p43 is a T3-dependent transcription factor of the mitochondrial genome, acting through dimeric complexes involving at least two other truncated forms of nuclear receptors, mtRXR and mtPPAR. P43 activation by T3 stimulates mitochondrial protein synthesis, respiratory chain activity and mitochondriogenesis. Through the mitochondrial/nuclear crosstalk, this direct T3 mitochondrial pathway influences the expression of nuclear genes involved in the regulation of cell proliferation and differentiation. In particular, in myoblasts, p43 overexpression stimulates terminal differentiation and induces a preferential expression of slow myosin, by down-regulating c-Myc expression and up-regulating calcineurin and myogenin expression. Comparison of the respective influences of the nuclear and mitochondrial T3 pathways demonstrates either both additivity (myoblast differentiation), complementarity (mitochondriogenesis, myoblast differentiation) or opposite influences (myosin expression), thus indicating that these two pathways introduce a fine-tuning of the hormone influence.
甲状腺激素对发育和代谢过程具有多种生理影响。寻找能够介导这种广泛调节作用的受体，导致了由两个不同基因c-erbAα（TRα）和c-erbAβ（TRβ）编码的三碘甲状腺原氨酸（T3）核受体的鉴定。最近，在线粒体中发现了三碘甲状腺原氨酸核受体TRα1的两种N端截短形式，分子量分别为43 kDa和28 kDa。它们通过TRα1转录本中发生的内部翻译起始位点合成，并根据一个非典型过程进入线粒体。在这些蛋白质的C端部分已鉴定出两个线粒体导入序列；此外，它们的N端部分不带负电荷，在这种导入过程中起允许作用。虽然p28的功能尚不清楚，但p43是线粒体基因组的T3依赖性转录因子，通过涉及至少两种其他截短形式核受体mtRXR和mtPPAR的二聚体复合物发挥作用。T3对p43的激活刺激线粒体蛋白质合成、呼吸链活性和线粒体生成。通过线粒体/细胞核的相互作用，这条直接的T3线粒体途径影响参与细胞增殖和分化调节的核基因的表达。特别是在成肌细胞中，p43的过表达通过下调c-Myc表达和上调钙调神经磷酸酶和肌细胞生成素表达，刺激终末分化并诱导慢肌球蛋白的优先表达。对核T3途径和线粒体T3途径各自影响的比较表明，它们既具有相加性（成肌细胞分化）、互补性（线粒体生成、成肌细胞分化），也具有相反的影响（肌球蛋白表达），因此表明这两条途径对激素影响进行了精细调节。
