Bax inhibitor-1 (BI1) conveys anti-apoptotic signals for mitochondria while prohibitin 2 (PHB2) is implicated in sustaining mitochondrial morphology and function. However, their regulatory roles in acute kidney injury (AKI) are largely unknown.

Methods: In human patients with AKI, levels of BI1 in urine and plasma were determined using ELISA. An experimental model of AKI was established using ATP depletion-mediated metabolic stress and ischemia-reperfusion injury (IRI) in primary tubule cells and BI1 transgenic mice, respectively. Western blots, ELISA, qPCR, immunofluorescence, RNA silencing, and domain deletion assay were employed to evaluate the roles of BI1 and PHB2 in the preservation of mitochondrial integrity.

Results: Levels of BI1 in urine and plasma were decreased in patients with AKI and its expression correlated inversely with renal function. However, reconstitution of BI1 in a murine AKI model was capable of alleviating renal failure, inflammation and tubular death. Further molecular scrutiny revealed that BI1 preserved mitochondrial genetic integrity, reduced mitochondrial oxidative stress, promoted mitochondrial respiration, inhibited excessive mitochondrial fission, improved mitophagy and suppressed mitochondrial apoptosis. Intriguingly, levels of the mitochondria-localized PHB2 were sustained by BI1 and knockdown of PHB2 abolished the mitochondrial- and renal- protective properties of BI1. Furthermore, BI1 promoted PHB2 retention within mitochondria through direct interaction with cytoplasmic PHB2 to facilitate its mitochondrial import. This was confirmed by the observation that the C-terminus of BI1 and the PHB domain of PHB2 were required for the BI1-PHB2 cross-linking.

Conclusion: Our data have unveiled an essential role of BI1 as a master regulator of renal tubule function through sustaining mitochondrial localization of PHB2, revealing novel therapeutic promises against AKI.

Bax抑制剂1（BI1）传递针对线粒体的抗凋亡信号，而禁止素2（PHB2）参与维持线粒体的形态和功能。但是，它们在急性肾损伤（AKI）中的调节作用尚不清楚。

方法：在人类AKI患者中，使用ELISA测定尿液和血浆中的BI1水平。使用ATP耗竭介导的代谢应激和缺血再灌注损伤（IRI）分别在原代小管细胞和BI1转基因小鼠中建立了AKI的实验模型。免疫印迹，ELISA，qPCR，免疫荧光，RNA沉默和域删除测定被用来评估BI1和PHB2在保持线粒体完整性中的作用。

结果： AKI患者尿液和血浆中BI1水平降低，其表达与肾功能呈负相关。但是，BI1的重组在鼠AKI模型中，Aβ能够减轻肾功能衰竭，炎症和肾小管死亡。进一步的分子检查显示，BI1保持了线粒体的遗传完整性，降低了线粒体的氧化应激，促进了线粒体的呼吸作用，抑制了线粒体的过度裂变，改善了线粒体的吞噬能力，​​并抑制了线粒体的凋亡。有趣的是，BI1维持了线粒体定位的PHB2的水平，而PHB2的敲除取消了BI1的线粒体和肾脏保护特性。此外，BI1通过与细胞质PHB2直接相互作用以促进其线粒体的导入而促进了PHB2在线粒体内的保留。通过观察证实，BI1-PHB2交联需要BI1的C末端和PHB2的PHB结构域。

结论：我们的数据揭示了BI1通过维持PHB2的线粒体定位，作为肾小管功能的主要调节剂的重要作用，揭示了针对AKI的新的治疗前景。