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

et al. (2008) Primary Coenzyme Q Deficiency in Pdss2 Mutant Mice Causes Isolated Renal Disease. PLoS Genet 4(4): e1000061. doi:10.1371/journal.pgen.1000061 Primary Coenzyme Q Deficiency in Pdss2 Mutant Mice Causes Isolated Renal Disease Min Peng 0 Marni J. Falk 0 Volker H. Haase 0 Rhonda King 0 Erzsebet Polyak 0 Mary Selak 0 Marc 0 Yudkoff 0 Wayne W. Hancock 0 Ray Meade 0 Ryoichi Saiki 0 Adam L. Lunceford 0 Catherine F. Clarke 0 David L. Gasser 0 David Beier, Harvard Medical School, United States of America 0 1 Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 2 Department of Pediatrics, Division of Human Genetics, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 3 Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 4 Mitochondrial Research Laboratory, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 5 Department of Pediatrics, Division of Metabolism, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 6 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 7 Biomedical Imaging Core Facility, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 8 Department of Chemistry and Biochemistry, University of California Los Angeles , Los Angeles, California , United States of America 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. - Funding: This work was supported by grants DK55852 (DLG), GM045952 and AG019777 (CC), and K08-DK073545 (MJF) from the National Institutes of Health. Histologic preparations were done in the Morphology Core for Molecular Studies in Digestive and Liver Diseases, which is supported by grant DK050306. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work Coenzyme Q (CoQ) is a benzoquinone molecule with a polyisoprenylated side chain that ranges from 6 to 10 isoprenyl units in length. It functions as an electron carrier in the mitochondrial respiratory chain, where it transports electrons from complexes I or II to complex III. The polyisoprenyl diphosphate synthases which form the isoprenyl side chain of CoQ in mice and humans are each heterotetramers of two protein subunits [1]. The genes that encode these subunits are now designated Pdss1 and Pdss2 in mice, and PDSS1 and PDSS2 in humans. Although its identity was not understood at the time, the first known mutation in the Pdss2 gene arose spontaneously in the CBA/CaH colony of Dr. Mary Lyon and was designated kidney disease (kd). Homozygotes for the kd allele develop a lethal disease characterized by tubulointerstitial nephritis, dilated tubules, and proteinuria [2]. Mutant kd/kd homozygotes appear healthy for at least the first 8 weeks of life, but histological examination of the kidneys beginning at about 12 weeks of life reveals a mononuclear cell infiltrate and tubular dilatation with proteinaceous casts in cortical areas. Over time this extends to involve the entire kidney with resultant renal failure [3,4,5]. Renal disease pathogenesis was initially thought to be immune mediated, rather than resulting from a structural or developmental defect [3,6]. However, we have since shown that the same renal disease, including leukocytic infiltration of macrophages and natural killer cells, develops spontaneously in kd/kd;Rag-12/2 double homozygotes lacking functional T and B lymphocytes [7]. Furthermore, mutant kd/kd mice are now recognized to have features of collapsing glomerulopathy (CG), a unique glomerular morphology in which hyperplastic and hypertrophic podocytes overlie collapsed capillary loops. While interstitial nephritis is often present in CG, no single definable pathogenic trigger for this disease has emerged [8]. Dysregulation of podocyte terminal differentiation in kd/kd mice was demonstrated by de novo expression of cyclin D1 (marking cell-cycle engagement) and KiCoenzyme 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 (...truncated)