IF 3.8 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Anke Schumann, Ainhoa Martinez-Pizarro, Eva Richard, Christoph Schell, Anna Laura Kössinger, Karina A Zeyer, Stefan Tholen, Oliver Schilling, Michael Barry, Björn Neubauer, Michael Köttgen, Luciana Hannibal, Lourdes R Desviat, Ute Spiekerkötter
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引用次数: 0

摘要

线粒体丙酰-CoA 羧化酶(PCC)的突变会导致丙酸尿症(PA)。慢性肾病(CKD)是一种已知的长期并发症。然而,良好的代谢控制和标准疗法并不能预防 CKD。CKD 的病理生理机制尚不清楚。我们研究了小鼠PA模型(Pcca-/-(A138T))的肾脏表型,以确定CKD的驱动机制。Pcca-/-(A138T)小鼠显示出升高的保留参数,并表达出随时间推移而进展的肾脏损伤标记物。对 Pcca-/-(A138T)小鼠肾脏的形态学评估表明,肾小管上皮细胞部分扁平化,肾小管囊性扩张。我们观察到肾线粒体超微结构发生了改变,而且对抗氧化应激的机制十分活跃。LC-MS/MS 分析证实了疾病特有的代谢特征,并揭示了线粒体通过 TCA 循环产生能量的紊乱。我们的研究发现,线粒体网络发生了改变,转向裂变,有丝分裂吞噬作用明显降低。我们观察到 PGC-1-α 的急剧减少,PGC-1-α 是调节线粒体功能的关键介质,也是线粒体裂变的反作用力。我们的研究结果表明,线粒体平衡和质量控制的损害与 PA 的 CKD 发展有关。除了目前的治疗策略外,针对已确定途径的治疗可能有助于改善 CKD。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias.

Mutations in the mitochondrial enzyme propionyl-CoA carboxylase (PCC) cause propionic aciduria (PA). Chronic kidney disease (CKD) is a known long-term complication. However, good metabolic control and standard therapy fail to prevent CKD. The pathophysiological mechanisms of CKD are unclear. We investigated the renal phenotype of a hypomorphic murine PA model (Pcca-/-(A138T)) to identify CKD-driving mechanisms. Pcca-/-(A138T) mice show elevated retention parameters and express markers of kidney damage progressing with time. Morphological assessment of the Pcca-/-(A138T) mouse kidneys indicated partial flattening of tubular epithelial cells and focal tubular-cystic dilation. We observed altered renal mitochondrial ultrastructure and mechanisms acting against oxidative stress were active. LC-MS/MS analysis confirmed disease-specific metabolic signatures and revealed disturbances in mitochondrial energy generation via the TCA cycle. Our investigations revealed altered mitochondrial networks shifted towards fission and a marked reduction of mitophagy. We observed a steep reduction of PGC-1-α, the key mediator modulating mitochondrial functions and a counter actor of mitochondrial fission. Our results suggest that impairment of mitochondrial homeostasis and quality control are involved in CKD development in PA. Therapeutic targeting of the identified pathways might help to ameliorate CKD in addition to the current treatment strategies.

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来源期刊
Scientific Reports
Scientific Reports Natural Science Disciplines-
CiteScore
7.50
自引率
4.30%
发文量
19567
审稿时长
3.9 months
期刊介绍: We publish original research from all areas of the natural sciences, psychology, medicine and engineering. You can learn more about what we publish by browsing our specific scientific subject areas below or explore Scientific Reports by browsing all articles and collections. Scientific Reports has a 2-year impact factor: 4.380 (2021), and is the 6th most-cited journal in the world, with more than 540,000 citations in 2020 (Clarivate Analytics, 2021). •Engineering Engineering covers all aspects of engineering, technology, and applied science. It plays a crucial role in the development of technologies to address some of the world''s biggest challenges, helping to save lives and improve the way we live. •Physical sciences Physical sciences are those academic disciplines that aim to uncover the underlying laws of nature — often written in the language of mathematics. It is a collective term for areas of study including astronomy, chemistry, materials science and physics. •Earth and environmental sciences Earth and environmental sciences cover all aspects of Earth and planetary science and broadly encompass solid Earth processes, surface and atmospheric dynamics, Earth system history, climate and climate change, marine and freshwater systems, and ecology. It also considers the interactions between humans and these systems. •Biological sciences Biological sciences encompass all the divisions of natural sciences examining various aspects of vital processes. The concept includes anatomy, physiology, cell biology, biochemistry and biophysics, and covers all organisms from microorganisms, animals to plants. •Health sciences The health sciences study health, disease and healthcare. This field of study aims to develop knowledge, interventions and technology for use in healthcare to improve the treatment of patients.
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