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LIX1-mediated changes in mitochondrial metabolism control the fate of digestive mesenchyme-derived cells
Redox Biology ( IF 10.7 ) Pub Date : 2022-08-13 , DOI: 10.1016/j.redox.2022.102431
Amandine Guérin 1 , Claire Angebault 1 , Sandrina Kinet 2 , Chantal Cazevieille 3 , Manuel Rojo 4 , Jérémy Fauconnier 1 , Alain Lacampagne 1 , Arnaud Mourier 4 , Naomi Taylor 2 , Pascal de Santa Barbara 1 , Sandrine Faure 1
Affiliation  

YAP1 and TAZ are transcriptional co-activator proteins that play fundamental roles in many biological processes, from cell proliferation and cell lineage fate determination to tumorigenesis. We previously demonstrated that Limb Expression 1 (LIX1) regulates YAP1 and TAZ activity and controls digestive mesenchymal progenitor proliferation. However, LIX1 mode of action remains elusive. Here, we found that endogenous LIX1 is localized in mitochondria and is anchored to the outer mitochondrial membrane through S-palmitoylation of cysteine 84, a residue conserved in all LIX1 orthologs. LIX1 downregulation altered the mitochondrial ultrastructure, resulting in a significantly decreased respiration and attenuated production of mitochondrial reactive oxygen species (mtROS). Mechanistically, knock-down impaired the stability of the mitochondrial proteins PHB2 and OPA1 that are found in complexes with mitochondrial-specific phospholipids and are required for cristae organization. Supplementation with unsaturated fatty acids counteracted the effects of knock-down on mitochondrial morphology and ultrastructure and restored YAP1/TAZ signaling. Collectively, our data demonstrate that LIX1 is a key regulator of cristae organization, modulating mtROS level and subsequently regulating the signaling cascades that control fate commitment of digestive mesenchyme-derived cells.

中文翻译:

LIX1介导的线粒体代谢变化控制消化间充质衍生细胞的命运

YAP1 和 TAZ 是转录共激活蛋白,在从细胞增殖、细胞谱系命运决定到肿瘤发生等许多生物过程中发挥着重要作用。我们之前证明 Limb Expression 1 (LIX1) 调节 YAP1 和 TAZ 活性并控制消化间充质祖细胞增殖。然而,LIX1 的作用模式仍然难以捉摸。在这里,我们发现内源性 LIX1 位于线粒体中,并通过半胱氨酸 84(所有 LIX1 直向同源物中保守的残基)的 S-棕榈酰化锚定在线粒体外膜上。 LIX1 下调改变了线粒体超微结构,导致呼吸作用显着降低,线粒体活性氧 (mtROS) 的产生减弱。从机制上讲,敲低损害了线粒体蛋白 PHB2 和 OPA1 的稳定性,这些蛋白存在于与线粒体特异性磷脂的复合物中,并且是嵴组织所必需的。补充不饱和脂肪酸可以抵消敲低对线粒体形态和超微结构的影响,并恢复 YAP1/TAZ 信号传导。总的来说,我们的数据表明 LIX1 是嵴组织的关键调节因子,调节 mtROS 水平并随后调节控制消化间充质衍生细胞命运承诺的信号级联。
更新日期:2022-08-13
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