Metabolic Derangement in Polycystic Kidney Disease Mouse Models Is Ameliorated by Mitochondrial-Targeted Antioxidants

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressively enlarging cysts. Here we elucidate the interplay between oxidative stress, mitochondrial dysfunction, and metabolic derangement using two mouse models of PKD1 mutation, PKD1RC/null and PKD1RC/RC. Mouse kidneys with PKD1 mutation have decreased mitochondrial complexes activity. Targeted proteomics analysis shows a significant decrease in proteins involved in the TCA cycle, fatty acid oxidation (FAO), respiratory complexes, and endogenous antioxidants. Overexpressing mitochondrial-targeted catalase (mCAT) using adeno-associated virus reduces mitochondrial ROS, oxidative damage, ameliorates the progression of PKD and partially restores expression of proteins involved in FAO and the TCA cycle. In human ADPKD cells, inducing mitochondrial ROS increased ERK1/2 phosphorylation and decreased AMPK phosphorylation, whereas the converse was observed with increased scavenging of ROS in the mitochondria. Treatment with the mitochondrial protective peptide, SS31, recapitulates the beneficial effects of mCAT, supporting its potential application as a novel therapeutic for ADPKD.常染色体显性遗传性多囊肾病（Autosomal dominant polycystic kidney disease, ADPKD）以进行性增大的囊肿为特征。本研究通过两种PKD1突变小鼠模型——PKD1RC/null与PKD1RC/RC，阐明了氧化应激、线粒体功能障碍与代谢紊乱之间的相互作用。携带PKD1突变的小鼠肾脏线粒体复合物活性显著降低。靶向蛋白质组学分析显示，三羧酸循环（TCA cycle）、脂肪酸氧化（fatty acid oxidation, FAO）、呼吸链复合物以及内源性抗氧化相关蛋白的表达量显著下调。借助腺相关病毒（adeno-associated virus, AAV）过表达线粒体靶向过氧化氢酶（mitochondrial-targeted catalase, mCAT），可降低线粒体活性氧（reactive oxygen species, ROS）水平、减轻氧化损伤，缓解多囊肾病的进展，并部分恢复FAO与TCA循环相关蛋白的表达。在人类ADPKD细胞中，诱导线粒体ROS可上调细胞外调节蛋白激酶1/2（extracellular signal-regulated kinase 1/2, ERK1/2）磷酸化水平并下调腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK）磷酸化水平，而增强线粒体ROS清除则会产生相反的效应。采用线粒体保护肽SS31进行处理，可重现mCAT的有益作用，提示其有望成为治疗ADPKD的新型潜在治疗手段。