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Mitochondrial Aurora kinase A induces mitophagy by interacting with MAP1LC3 and Prohibitin 2

Abstract : Epithelial and haematologic tumours often show the overexpression of the serine/threonine kinase AURKA. Recently, AURKA was shown to localise at mitochondria, where it regulates mitochondrial dynamics and ATP production. Here we define the molecular mechanisms of AURKA in regulating mitochondrial turnover by mitophagy. When overexpressed, AURKA induces the rupture of the Outer Mitochondrial Membrane in a proteasome-dependent manner. Then, AURKA triggers the degradation of Inner Mitochondrial Membrane (IMM)/matrix proteins by interacting with core components of the autophagy pathway. On the IMM, the kinase forms a tripartite complex with MAP1LC3 and the mitophagy receptor PHB2. This complex is necessary to trigger mitophagy in a PARK2/Parkin-independent manner. The formation of the tripartite complex is induced by the phosphorylation of PHB2 on Ser39, which is required for MAP1LC3 to interact with PHB2. Last, treatment with the PHB2 ligand Xanthohumol blocks AURKA-induced mitophagy by destabilising the tripartite complex. This treatment also restores normal ATP production levels. Altogether, these data provide evidence for a previously undetected role of AURKA in promoting mitophagy through the interaction with PHB2 and MAP1LC3. This work paves the way to the use of function-specific pharmacological inhibitors to counteract the effects of the overexpression of AURKA in cancer.
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-02566766
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Submitted on : Thursday, May 7, 2020 - 12:26:56 PM
Last modification on : Tuesday, October 19, 2021 - 11:39:55 AM

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Giulia Bertolin, Marie-Clotilde Alves-Guerra, Angélique Chéron, Agnes Burel, Claude Prigent, et al.. Mitochondrial Aurora kinase A induces mitophagy by interacting with MAP1LC3 and Prohibitin 2. 2021. ⟨hal-02566766⟩

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