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Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease.

Peng M, Falk MJ, Haase VH, King R, Polyak E, Selak M, Yudkoff M, Hancock WW, Meade R, Saiki R, Lunceford AL, Clarke CF, Gasser DL - PLoS Genet. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.

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 Pdss2(kd/kd) genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2(kd/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,Pdss2(loxP/loxP) knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes. Liver-conditional B6.Alb/cre,Pdss2(loxP/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.

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Pdss2 Mutants Have Altered Amino Acid Profiles in Liver.Pdss2 mutants have altered amino acid profiles in liver. Quantitative liver amino acid analysis detects significant differences in B6.Pdss2kd/kd missense mutants compared with B6 controls (Panels A and B), as well as in B6.Alb/cre,Pdss2loxP/loxP mutants compared with B6.Pdss2loxP/loxP controls (Panels C and D). To better demonstrate differences in all amino acids, results for three amino acids in highest abundance are shown separately (Panels B and D) with a greater scale compared to that used for the remainder of the amino acids present in relatively lower abundance (Panels A and C). Values represent mean +/− SEM. Statistical analyses comparing mutants and controls were performed by Student's t-test, where * indicates p<0.05 and ** indicates p<0.01.
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pgen-1000061-g008: Pdss2 Mutants Have Altered Amino Acid Profiles in Liver.Pdss2 mutants have altered amino acid profiles in liver. Quantitative liver amino acid analysis detects significant differences in B6.Pdss2kd/kd missense mutants compared with B6 controls (Panels A and B), as well as in B6.Alb/cre,Pdss2loxP/loxP mutants compared with B6.Pdss2loxP/loxP controls (Panels C and D). To better demonstrate differences in all amino acids, results for three amino acids in highest abundance are shown separately (Panels B and D) with a greater scale compared to that used for the remainder of the amino acids present in relatively lower abundance (Panels A and C). Values represent mean +/− SEM. Statistical analyses comparing mutants and controls were performed by Student's t-test, where * indicates p<0.05 and ** indicates p<0.01.

Mentions: Altered amino acid metabolism is further supported by significant concentration differences among multiple amino acids quantified in livers of B6.Alb/cre,Pdss2loxP/loxP mutants (Figure 8, Panels C and D). Hepatic glutamate was lowered to less than half the control value (p<0.01; Figure 8, Panel D). Glutamate depletion could account for decreased levels of glutamine and alanine (Figure 8, Panel D) that derive from glutamate via glutamine synthetase and alanine aminotransferase, respectively. Similarly, a loss of glutamate could lower hepatic concentrations of phenyalanine, methionine, leucine, isoleucine and valine (Figure 8, Panel C), each of which forms from glutamate by a specific transaminase. The total absence of citrulline (Figure 8, Panel C) suggests ureagenesis is compromised in Pdss2 mutant mice. Similarly, the sole amino acid to be significantly increased was the urea cycle precursor, aspartate (Figure 8, Panel C), with a sharp reduction in the glutamate∶aspartate ratio (1∶4 vs 4∶1) of mutant vs control liver.


Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease.

Peng M, Falk MJ, Haase VH, King R, Polyak E, Selak M, Yudkoff M, Hancock WW, Meade R, Saiki R, Lunceford AL, Clarke CF, Gasser DL - PLoS Genet. (2008)

Pdss2 Mutants Have Altered Amino Acid Profiles in Liver.Pdss2 mutants have altered amino acid profiles in liver. Quantitative liver amino acid analysis detects significant differences in B6.Pdss2kd/kd missense mutants compared with B6 controls (Panels A and B), as well as in B6.Alb/cre,Pdss2loxP/loxP mutants compared with B6.Pdss2loxP/loxP controls (Panels C and D). To better demonstrate differences in all amino acids, results for three amino acids in highest abundance are shown separately (Panels B and D) with a greater scale compared to that used for the remainder of the amino acids present in relatively lower abundance (Panels A and C). Values represent mean +/− SEM. Statistical analyses comparing mutants and controls were performed by Student's t-test, where * indicates p<0.05 and ** indicates p<0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2291193&req=5

pgen-1000061-g008: Pdss2 Mutants Have Altered Amino Acid Profiles in Liver.Pdss2 mutants have altered amino acid profiles in liver. Quantitative liver amino acid analysis detects significant differences in B6.Pdss2kd/kd missense mutants compared with B6 controls (Panels A and B), as well as in B6.Alb/cre,Pdss2loxP/loxP mutants compared with B6.Pdss2loxP/loxP controls (Panels C and D). To better demonstrate differences in all amino acids, results for three amino acids in highest abundance are shown separately (Panels B and D) with a greater scale compared to that used for the remainder of the amino acids present in relatively lower abundance (Panels A and C). Values represent mean +/− SEM. Statistical analyses comparing mutants and controls were performed by Student's t-test, where * indicates p<0.05 and ** indicates p<0.01.
Mentions: Altered amino acid metabolism is further supported by significant concentration differences among multiple amino acids quantified in livers of B6.Alb/cre,Pdss2loxP/loxP mutants (Figure 8, Panels C and D). Hepatic glutamate was lowered to less than half the control value (p<0.01; Figure 8, Panel D). Glutamate depletion could account for decreased levels of glutamine and alanine (Figure 8, Panel D) that derive from glutamate via glutamine synthetase and alanine aminotransferase, respectively. Similarly, a loss of glutamate could lower hepatic concentrations of phenyalanine, methionine, leucine, isoleucine and valine (Figure 8, Panel C), each of which forms from glutamate by a specific transaminase. The total absence of citrulline (Figure 8, Panel C) suggests ureagenesis is compromised in Pdss2 mutant mice. Similarly, the sole amino acid to be significantly increased was the urea cycle precursor, aspartate (Figure 8, Panel C), with a sharp reduction in the glutamate∶aspartate ratio (1∶4 vs 4∶1) of mutant vs control liver.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.

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 Pdss2(kd/kd) genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2(kd/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,Pdss2(loxP/loxP) knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes. Liver-conditional B6.Alb/cre,Pdss2(loxP/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.

Show MeSH
Related in: MedlinePlus