Primary Coenzyme Q Deficiency in Pdss2 Mutant Mice Causes Isolated Renal Disease

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Abstract
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.