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Pré-Publication, Document De Travail Année : 2022

LIX1 controls digestive mesenchyme-derived cell fate decision by regulating cristae organization in mitochondria

Sandrina Kinet
  • Fonction : Auteur
Chantal Cazevieille
Manuel Rojo
Arnaud Mourier
Naomi Taylor
Sandrine Faure

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.
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Dates et versions

hal-03520572 , version 1 (11-01-2022)

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Amandine Guerin, Claire Angebault, Sandrina Kinet, Chantal Cazevieille, Manuel Rojo, et al.. LIX1 controls digestive mesenchyme-derived cell fate decision by regulating cristae organization in mitochondria. 2022. ⟨hal-03520572⟩
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