LIX1 controls digestive mesenchyme-derived cell fate decision by regulating cristae organization in mitochondria
Résumé
Limb Expression 1 (LIX1) is a master regulator of digestive mesenchymal progenitor and GastroIntestinal Stromal Tumor (GIST) cell proliferation by controlling the expression of the Hippo effectors YAP1/TAZ and KIT. However, the underlying mechanisms of these LIX1- mediated regulations and tumor promotion remain to be elucidated. Here, we report that LIX1 is S-palmitoylated on cysteine 84 and localized in mitochondria. LIX1 knock-down affects the mitochondrial ultrastructure, resulting in decreased respiration and mitochondrial reactive oxygen species production. This is sufficient to downregulate YAP1/TAZ and reprogram KIT- positive GIST cells towards the smooth muscle cell lineage with reduced proliferative and invasive capacities. Mechanistically, LIX1 knock-down impairs 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 counteracts the effects of LIX1 knock-down on mitochondrial morphology and ultrastructure, restores YAP1/TAZ signaling, and consequently KIT levels. Altogether, our findings demonstrate that LIX1 contributes to GIST aggressive potential by modulating YAP1/TAZ and KIT levels, a process that depends on mitochondrial remodeling. Our work brings new insights into the mechanisms that could be targeted in tumors in which YAP1 and TAZ are implicated.
Domaines
Sciences du Vivant [q-bio]
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