Aldehyde dehydrogenase 2 alleviates mitochondrial dysfunction by promoting PGC-1α-mediated biogenesis in acute kidney injury.
Aldehyde dehydrogenase 2 alleviates mitochondrial dysfunction by promoting PGC-1α-mediated biogenesis in acute kidney injury.
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DOI：
10.1038/s41419-023-05557-x
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发表时间：
2023-01-20
影响因子：
9
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中科院分区：
文献类型：
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肾小管上皮细胞是高耗能细胞类型之一，主要依赖线粒体供能。乙醛脱氢酶2（ALDH 2）是参与酒精代谢和线粒体氧化ATP产生的关键酶;然而，其在急性肾损伤（阿基）中线粒体稳态中的功能尚不清楚。在这里，我们发现ALDH 2的表达主要是减少顺铂或马来酸（MA）模型在体内和体外。ALDH 2基因敲除（KO）小鼠在顺铂注射后表现出加重的肾损害和肾小管上皮细胞凋亡。相比之下，ALDH 2激活减轻阿基和肾小管细胞凋亡在顺铂和MA诱导的模型。RNA测序显示，在MA诱导的小鼠中，在Alda-1预处理后，氧化磷酸化途径在肾组织中正富集。ALDH 2激活恢复线粒体结构，线粒体膜电位和呼吸速率，但下调MA诱导的小鼠和人肾近端肾小管上皮细胞（HK-2）的糖酵解。从机制上讲，免疫共沉淀试验表明，ALDH 2与过氧化物酶体增殖物-γ共激活因子-1 α（PGC-1α）相互作用，PGC-1α是线粒体生物合成的主要调节因子，并促进其核转位。随后，PGC-1α敲低几乎取消了ALDH 2激活对MA诱导的肾小管上皮细胞损伤的改善。因此，我们的研究表明，ALDH 2激活通过增强PGC-1α介导的线粒体生物合成来减轻阿基中的线粒体功能障碍。因此，ALDH 2可能作为预防阿基进展的潜在治疗靶点。
Renal tubular epithelial cells are one of the high energy-consuming cell types, which mainly depend on mitochondrial energy supply. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme that is involved in alcohol metabolism and mitochondrial oxidative ATP production; however, its function in mitochondrial homoeostasis in acute kidney injury (AKI) is unclear. Here, we found that ALDH2 expression was predominantly decreased in cisplatin or maleic acid (MA) models both in vivo and in vitro. ALDH2 knockout (KO) mice exhibited exacerbated kidney impairment and apoptosis of tubular epithelial cells after cisplatin injection. In contrast, ALDH2 activation alleviated AKI and tubular cell apoptosis in both cisplatin- and MA-induced models. RNA sequencing revealed that the oxidative phosphorylation pathway was positively enriched in the renal tissues after Alda-1 pre-treatment in MA-induced mice. ALDH2 activation restored mitochondrial structure, mitochondrial membrane potential, and respiration rate, but downregulated glycolysis in MA-induced mice and human renal proximal tubular epithelial (HK-2) cells. Mechanistically, co-immunoprecipitation assays revealed that ALDH2 interacts with peroxisomal proliferator-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, and advanced its nuclear translocation. Subsequently, PGC-1α knockdown almost abolished the improvement of ALDH2 activation on MA-induced tubular epithelial cells damage. Thus, our study revealed that ALDH2 activation alleviated mitochondrial dysfunction in AKI by enhancing PGC-1α-mediated mitochondrial biogenesis. Hence, ALDH2 may act as a potential therapeutic target to prevent AKI progression.
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