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 disappearance of Outer Mitochondrial Membrane proteins by the proteasome. 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.

中文翻译：

---

线粒体极光激酶A通过与MAP1LC3和Prohibitin 2相互作用诱导线粒体吞噬

上皮和血液肿瘤通常表现出丝氨酸/苏氨酸激酶AURKA的过表达。最近，AURKA被证明位于线粒体，它调节线粒体动力学和ATP产生。在这里，我们定义了AURKA通过线粒体调控线粒体更新的分子机制。当过表达时，AURKA会诱导蛋白酶体使外部线粒体膜蛋白消失。然后，AURKA通过与自噬途径的核心成分相互作用，触发内线粒体膜（IMM）/基质蛋白的降解。在IMM上，该激酶与MAP1LC3和线粒体受体PHB2形成三重复合物。该复合物对于以独立于PARK2 / Parkin的方式触发线粒体化是必需的。三方复合物的形成是由PH39在Ser39上的磷酸化诱导的，这是MAP1LC3与PHB2交互所必需的。最后，用PHB2配体黄腐酚进行处理会破坏三方复合物的稳定性，从而阻止AURKA诱导的线粒体吞噬。该处理还可以恢复正常的ATP产生水平。总而言之，这些数据提供了AURKA在通过与PHB2和MAP1LC3相互作用促进线粒体吞噬中尚未发现的作用的证据。这项工作为使用功能特异性药理抑制剂来抵消AURKA过表达在癌症中的作用铺平了道路。这些数据提供了AURKA在通过与PHB2和MAP1LC3相互作用促进线粒体吞噬中尚未发现的作用的证据。这项工作为使用功能特异性药理抑制剂来抵消AURKA过表达在癌症中的作用铺平了道路。这些数据提供了AURKA在通过与PHB2和MAP1LC3相互作用促进线粒体吞噬中尚未发现的作用的证据。这项工作为使用功能特异性药理抑制剂来抵消AURKA过表达在癌症中的作用铺平了道路。