Metabolic derangement in polycystic kidney disease mouse models is ameliorated by mitochondrial-targeted antioxidants.
Metabolic derangement in polycystic kidney disease mouse models is ameliorated by mitochondrial-targeted antioxidants.
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DOI：
10.1038/s42003-021-02730-w
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发表时间：
2021-10-20
影响因子：
5.9
通讯作者：
Dai DF
中科院分区：
文献类型：
--
作者：
Daneshgar N;Baguley AW;Liang PI;Wu F;Chu Y;Kinter MT;Benavides GA;Johnson MS;Darley-Usmar V;Zhang J;Chan KS;Dai DF
常染色体显性遗传性多囊肾病(ADPKD)以进行性增大为特征。在这里，我们使用两种PKD1RC/Null和PKD1RC/RC突变的小鼠模型来阐明氧化应激、线粒体功能障碍和代谢紊乱之间的相互作用。PKD1突变的小鼠肾脏线粒体复合体活性降低。靶向蛋白质组学分析显示，参与三氯乙酸循环、脂肪酸氧化(FAO)、呼吸复合体和内源性抗氧化剂的蛋白质显著减少。用腺相关病毒过表达线粒体靶向过氧化氢酶(MCAT)可以减少线粒体ROS，减少氧化损伤，改善PKD的进展，并部分恢复FAO和TCA循环中涉及的蛋白质的表达。在人ADPKD细胞中，诱导线粒体ROS使ERK1/2磷酸化增加，AMPK磷酸化降低，而线粒体ROS清除增加则相反。线粒体保护肽SS31的治疗概括了MCAT的有益效果，支持其作为ADPKD的一种新疗法的潜在应用。Daneshgar等人。探讨线粒体功能障碍在ADPKD中的作用以及线粒体保护剂作为潜在治疗药物的作用。作者报道了ADPKD中线粒体复合体活性降低以及线粒体和代谢蛋白表达下调，并建议MCAT过表达或SS31治疗以减缓囊变发生。
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. Daneshgar et al. investigated the role of mitochondrial dysfunction in ADPKD and mitochondria protective agents as potential therapeutics. The authors reported decreased mitochondrial complex activity and downregulation of mitochondrial and metabolic proteins in ADPKD, and proposed mCAT overexpression or SS31 treatment to slow cystogenesis.
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影响因子：
3.3
作者：
Padovano V;Kuo IY;Stavola LK;Aerni HR;Flaherty BJ;Chapin HC;Ma M;Somlo S;Boletta A;Ehrlich BE;Rinehart J;Caplan MJ
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Caplan MJ
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9.9
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影响因子：
13.6
作者：
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通讯作者：
Guggino, WB
影响因子：
15.9
作者：
Hopp, Katharina;Ward, Christopher J.;Harris, Peter C.
通讯作者：
Harris, Peter C.