Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a slowly progressive disease characterized by the relentless growth of renal cysts throughout the life of affected individuals. Early evidence suggested that the epithelia lining the cysts share neoplastic features, leading to the definition of PKD as a "neoplasm in disguise". Recent work from our and other laboratories has identified a profound metabolic reprogramming in PKD, similar to the one reported in cancer and consistent with the reported increased proliferation. Multiple lines of evidence suggest that aerobic glycolysis (a Warburg-like effect) is present in the disease, along with other metabolic dysfunctions such as an increase in the pentose phosphate pathway, in glutamine anaplerosis and fatty acid biosynthesis, while fatty acid oxidation and oxidative phosphorylation (OXPHOS) are decreased. In addition to glutamine, other amino acid-related pathways appear altered, including asparagine and arginine. The precise origin of the metabolic alterations is not entirely clear, but two hypotheses can be formulated, not mutually exclusive. First, the polycystins have been recently shown to regulate directly mitochondrial function and structure either by regulating Ca2+ uptake in mitochondria at the Mitochondria Associated Membranes (MAMs) of the Endoplasmic Reticulum, or by a direct translocation of a small fragment of the protein into the matrix of mitochondria. One alternative possibility is that metabolic and mitochondrial dysfunctions in ADPKD are secondary to the de-regulation of proliferation, driven by the multiple signaling pathways identified in the disease, which include mTORC1 and AMPK among the most relevant. While the precise mechanisms underlying these novel alterations identified in ADPKD will need further investigation, it is evident that they offer a great opportunity for novel interventions in the disease.

中文翻译：

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代谢重编程和线粒体在多囊性肾脏疾病中的作用。

常染色体显性多囊肾病（ADPKD）是一种缓慢进展的疾病，其特征是在整个受影响个体的整个生命过程中，肾囊肿持续不断地生长。早期证据表明，囊肿内衬的上皮细胞具有肿瘤特征，从而将PKD定义为“变相的肿瘤”。我们和其他实验室的最新工作已经确定了PKD中的一种深刻的代谢重编程，类似于癌症中报道的一种，并且与报道的增殖增加相一致。多种证据表明，该疾病中存在有氧糖酵解（类似Warburg的效应），以及其他代谢功能异常，例如戊糖磷酸途径增加，谷氨酰胺过剩和脂肪酸生物合成，而脂肪酸氧化和氧化磷酸化（OXPHOS）减少。除谷氨酰胺外，其他与氨基酸有关的途径也发生了改变，包括天冬酰胺和精氨酸。代谢改变的确切来源尚不完全清楚，但是可以提出两个假设，而不是相互排斥的。首先，最近已证明，多囊藻毒素通过调节内质网线粒体相关膜（MAM）线粒体中的Ca2 +吸收来直接调节线粒体的功能和结构，或直接将蛋白的小片段转移到基质中线粒体。一种替代的可能性是，ADPKD中的代谢和线粒体功能障碍是增殖失调的继发因素，由疾病中确定的多种信号通路驱动，其中最相关的包括mTORC1和AMPK。尽管在ADPKD中鉴定出这些新颖改变的确切机制尚需进一步研究，但很显然，它们为对该疾病进行新颖干预提供了巨大的机会。