肾小管上皮细胞（RTECs）代谢重编程的劣化和线粒体自噬的抑制加重脓毒症急性肾损伤（SAKI）。去琥珀酰化酶SIRT5和ATP酶抑制因子（ATPIF1）均可优化代谢重编程和促进线粒体自噬，但二者的关系及其在SAKI发生中的作用和机制尚不清楚。申请人前期基于琥珀酰化组学和生物信息学的研究发现SAKI后ATPIF1过度琥珀酰化可能加重SAKI。预实验证实抑制SIRT5后ATPIF1超琥珀酰化，伴能量生成不足且线粒体自噬抑制。我们假设SIRT5通过去琥珀酰化ATPIF1调控RTECs的代谢重编程和线粒体自噬，其活性降低是SAKI发生的分子机制。本项目拟：①构建SAKI动物模型并对SIRT5基因敲除/入，明确SIRT5对代谢重编程和线粒体自噬的影响；②复制SAKI细胞模型并突变ATPIF1琥珀酰化位点，探讨SIRT5减轻SAKI的机制依赖于去琥珀酰化ATPIF1。为阐明SAKI的机制提供新证据。

The degradation of metabolic reprogramming and inhibition of mitophagy in renal tubular epithelial cells (RTECs) aggravates sepsis-induced acute kidney injury (SAKI). It has been reported that both succinylase SIRT5 and ATPase inhibitor (ATPIF1) can optimize metabolic reprogramming and promote mitophagy; However, the relationship between SIRT5 and ATPIF1, and its role and mechanism in the pathogenesis of SAKI are still unclear. Our preliminary work based on succinyl genomics and bioinformatics studies found that ATPIF1 hyper-succinylation after SAKI may aggravate SAKI. Pre-experiments confirmed that inhibition of SIRT5 results in hyper-succinylation of ATPIF1, accompanying with insufficient energy production and inhibition of mitophagy. We hypothesized that SIRT5 regulates the metabolic reprogramming and mitophagy by de-succinylating ATPIF1, and the reduced SIRT5 activity is the molecular mechanism of SAKI. This project intends to: ① construct SAKI animal model and SIRT5 knockout /knochin mice to confirm the effects of SIRT5 on metabolic reprogramming and mitophagy; ② reproduce SAKI cell model and mutate ATPIF1 succinylation site to explore The that the mechanism of SIRT5 alleviation on ameliorating SAKI relying on desuccinylation of ATPIF1. Based on the work above, we try to provide novel evidence for elucidating the mechanism of SAKI.