Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease.
Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease.
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PDSS2突变小鼠的原发性辅酶缺乏会引起孤立的肾脏疾病。
DOI：
10.1371/journal.pgen.1000061
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发表时间：
2008-04-25
期刊：
影响因子：
4.5
通讯作者：
Gasser, David L.
中科院分区：
文献类型：
--
作者：
Peng, Min;Falk, Marni J.;Haase, Volker H.;King, Rhonda;Polyak, Erzsebet;Selak, Mary;Yudkoff, Marc;Hancock, Wayne W.;Meade, Ray;Saiki, Ryoichi;Lunceford, Adam L.;Clarke, Catherine F.;Gasser, David L.
辅酶 Q (CoQ) 是呼吸链中重要的电子载体，其缺乏与多种人类线粒体疾病表现有关。其多步骤生物合成涉及在需要由 PDSS1 和 PDSS2 编码的酶的反应中产生聚异戊二烯二磷酸酯。在人类中，这些基因中的任何一个的纯合突变都会导致严重的神经肌肉疾病，在 PDSS2 缺陷中会出现肾病综合征。我们现在表明，具有错义 Pdss2kd/kd 基因型的小鼠中推测的自身免疫性肾病可归因于线粒体 CoQ 生物合成缺陷。 B6.Pdss2kd/kd 突变体肾匀浆中 CoQ9 和 CoQ10 的水平显着低于 B6 对照小鼠。疾病表现特别起源于肾小球足细胞，因为在 Podocin/cre、Pdss2loxP/loxP 敲除小鼠中观察到肾脏疾病，但在针对肾小管上皮、单核细胞或肝细胞的条件敲除小鼠中则没有观察到肾脏疾病。肝脏条件 B6.Alb/cre、Pdss2loxP/loxP 敲除小鼠没有明显的疾病，尽管转录谱和氨基酸定量证明，它们的肝脏 CoQ9 水平检测不到、呼吸能力受损、中间代谢显着改变。这些数据表明，CoQ 缺乏的疾病表现与组织特异性呼吸能力阈值相关，肾小球足细胞对 Pdss2 损伤表现出最大的敏感性。辅酶 Q 是线粒体呼吸链的重要组成部分，线粒体呼吸链是细胞产生能量的过程。人类辅酶 Q 缺乏会导致多种疾病表现，影响神经系统、肌肉和肾脏。在这里，我们证明，由于 Pdss2 突变而无法制造辅酶 Q 是导致小鼠致命性肾病的原因，此前人们认为这种疾病是由自身免疫过程引起的。通过研究自发发生的错义突变体和一系列仅针对肝脏、肾脏或巨噬细胞的辅酶 Q 缺乏症产生的突变体，我们发现引起肾脏疾病的特定细胞类型是肾小球足细胞。这些动物没有明显的其他疾病表现。然而，我们对这些小鼠肝脏的分析表明，它们的辅酶 Q 显着消耗，线粒体呼吸链功能受损，并且许多其他基本代谢过程受到干扰。在这些小鼠和之前报道的线虫模型中都观察到了类似的原发性线粒体功能障碍细胞改变的微阵列模式，这表明原发性呼吸链功能的共同细胞特征可能存在于整个进化过程中。
Coenzyme Q (CoQ) is an essential electron carrier in the respiratory chain whose deficiency has been implicated in a wide variety of human mitochondrial disease manifestations. Its multi-step biosynthesis involves production of polyisoprenoid diphosphate in a reaction that requires the enzymes be encoded by PDSS1 and PDSS2. Homozygous mutations in either of these genes, in humans, lead to severe neuromuscular disease, with nephrotic syndrome seen in PDSS2 deficiency. We now show that a presumed autoimmune kidney disease in mice with the missense Pdss2kd/kd genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2kd/kd mutants were significantly lower than those in B6 control mice. Disease manifestations originate specifically in glomerular podocytes, as renal disease is seen in Podocin/cre,Pdss2loxP/loxP knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes. Liver-conditional B6.Alb/cre,Pdss2loxP/loxP knockout mice have no overt disease despite demonstration that their livers have undetectable CoQ9 levels, impaired respiratory capacity, and significantly altered intermediary metabolism as evidenced by transcriptional profiling and amino acid quantitation. These data suggest that disease manifestations of CoQ deficiency relate to tissue-specific respiratory capacity thresholds, with glomerular podocytes displaying the greatest sensitivity to Pdss2 impairment. Coenzyme Q is a critical component of the mitochondrial respiratory chain, the process by which cells make energy. Coenzyme Q deficiency in humans causes a wide range of disease manifestations affecting the nervous system, muscles, and kidneys. Here, we show that the failure to make Coenzyme Q due to a Pdss2 mutation is the cause of a lethal kidney disease in mice that was previously thought to result from an autoimmune process. Studying both a spontaneously occurring missense mutant and a series of mutants generated to have the Coenzyme Q deficiency targeted solely to liver, kidney, or macrophages, we show that the specific cell type in which the kidney disease arises is the glomerular podocyte. No other manifestations of disease are evident in these animals. However, our analysis of livers from these mice reveals that they have significant depletion of Coenzyme Q, impairment of mitochondrial respiratory chain function, and disturbance of many other basic metabolic processes. Similar microarray patterns of cellular alterations to primary mitochondrial dysfunction were seen both in these mice and in a previously reported nematode model, suggesting that a common cellular profile of primary respiratory chain function may exist across evolution.
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