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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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CoQ Measurements in Pdss2 Missense, Conditional Knockout, and Strain-Matched Control Mice.CoQ measurements in Pdss2kd/kd; Podocin/cre,Pdss2loxPloxP; PEPCK/cre,Pdss2loxPloxP; Alb/cre,Pdss2loxP/loxP; and strain-matched control mice (B6 and B6.Pdss2loxPloxP). A, Kidney levels of CoQ9 and CoQ10 are significantly lower in B6.Pdss2kd/kd (missense) mice than in B6 control mice. B, Kidney levels of CoQ9 and CoQ10 are similar in B6.Podocin/cre,Pdss2loxPloxP; B6.PEPCK/cre,Pdss2loxPloxP; B6.Alb/cre,Pdss2loxP/loxP; and control mice. The 92-day-old controls are B6.Pdss2loxP/+, and the 94-day-old control is B6.Pdss2loxP/loxP. C, Liver levels of CoQ9 in B6.Alb/cre,Pdss2loxP/loxP mice were below 30 picomoles/mg protein (*) while these same levels in B6.Podocin/cre,Pdss2loxPloxP and B6.PEPCK/cre,Pdss2loxPloxP mice were similar to those in control mice. The strains of the control mice in are the same as those in panel B.
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pgen-1000061-g005: CoQ Measurements in Pdss2 Missense, Conditional Knockout, and Strain-Matched Control Mice.CoQ measurements in Pdss2kd/kd; Podocin/cre,Pdss2loxPloxP; PEPCK/cre,Pdss2loxPloxP; Alb/cre,Pdss2loxP/loxP; and strain-matched control mice (B6 and B6.Pdss2loxPloxP). A, Kidney levels of CoQ9 and CoQ10 are significantly lower in B6.Pdss2kd/kd (missense) mice than in B6 control mice. B, Kidney levels of CoQ9 and CoQ10 are similar in B6.Podocin/cre,Pdss2loxPloxP; B6.PEPCK/cre,Pdss2loxPloxP; B6.Alb/cre,Pdss2loxP/loxP; and control mice. The 92-day-old controls are B6.Pdss2loxP/+, and the 94-day-old control is B6.Pdss2loxP/loxP. C, Liver levels of CoQ9 in B6.Alb/cre,Pdss2loxP/loxP mice were below 30 picomoles/mg protein (*) while these same levels in B6.Podocin/cre,Pdss2loxPloxP and B6.PEPCK/cre,Pdss2loxPloxP mice were similar to those in control mice. The strains of the control mice in are the same as those in panel B.

Mentions: CoQ content was determined in lipid extracts of tissue homogenates from livers and kidneys dissected from mutant and control mice. As shown in Figure 5 (Panel A), there was a significant reduction in CoQ9 and CoQ10 levels in the kidneys of B6.Pdss2kd/kd mice compared to age-matched B6 controls. There were no significant differences in kidney CoQ9 content between the B6, B6.Pdss2loxP/+, or B6.Pdss2loxP/loxP control mice (Panels A and B). Neither the B6.Podocin/cre,Pdss2loxP/loxP nor the B6.PEPCK/cre,Pdss2loxP/loxP mice had a significant reduction in the CoQ9 levels of total liver or kidney homogenates (Panels B and C), which is consistent with the fact that only a small subset of cells were affected by these targeted disruptions. However, the B6.Alb/cre,Pdss2loxP/loxP mice had less than 30 pmol CoQ9 per mg liver protein, which would be expected if most hepatic cells were affected by the albumin promoter-driven Cre expression.


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)

CoQ Measurements in Pdss2 Missense, Conditional Knockout, and Strain-Matched Control Mice.CoQ measurements in Pdss2kd/kd; Podocin/cre,Pdss2loxPloxP; PEPCK/cre,Pdss2loxPloxP; Alb/cre,Pdss2loxP/loxP; and strain-matched control mice (B6 and B6.Pdss2loxPloxP). A, Kidney levels of CoQ9 and CoQ10 are significantly lower in B6.Pdss2kd/kd (missense) mice than in B6 control mice. B, Kidney levels of CoQ9 and CoQ10 are similar in B6.Podocin/cre,Pdss2loxPloxP; B6.PEPCK/cre,Pdss2loxPloxP; B6.Alb/cre,Pdss2loxP/loxP; and control mice. The 92-day-old controls are B6.Pdss2loxP/+, and the 94-day-old control is B6.Pdss2loxP/loxP. C, Liver levels of CoQ9 in B6.Alb/cre,Pdss2loxP/loxP mice were below 30 picomoles/mg protein (*) while these same levels in B6.Podocin/cre,Pdss2loxPloxP and B6.PEPCK/cre,Pdss2loxPloxP mice were similar to those in control mice. The strains of the control mice in are the same as those in panel B.
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pgen-1000061-g005: CoQ Measurements in Pdss2 Missense, Conditional Knockout, and Strain-Matched Control Mice.CoQ measurements in Pdss2kd/kd; Podocin/cre,Pdss2loxPloxP; PEPCK/cre,Pdss2loxPloxP; Alb/cre,Pdss2loxP/loxP; and strain-matched control mice (B6 and B6.Pdss2loxPloxP). A, Kidney levels of CoQ9 and CoQ10 are significantly lower in B6.Pdss2kd/kd (missense) mice than in B6 control mice. B, Kidney levels of CoQ9 and CoQ10 are similar in B6.Podocin/cre,Pdss2loxPloxP; B6.PEPCK/cre,Pdss2loxPloxP; B6.Alb/cre,Pdss2loxP/loxP; and control mice. The 92-day-old controls are B6.Pdss2loxP/+, and the 94-day-old control is B6.Pdss2loxP/loxP. C, Liver levels of CoQ9 in B6.Alb/cre,Pdss2loxP/loxP mice were below 30 picomoles/mg protein (*) while these same levels in B6.Podocin/cre,Pdss2loxPloxP and B6.PEPCK/cre,Pdss2loxPloxP mice were similar to those in control mice. The strains of the control mice in are the same as those in panel B.
Mentions: CoQ content was determined in lipid extracts of tissue homogenates from livers and kidneys dissected from mutant and control mice. As shown in Figure 5 (Panel A), there was a significant reduction in CoQ9 and CoQ10 levels in the kidneys of B6.Pdss2kd/kd mice compared to age-matched B6 controls. There were no significant differences in kidney CoQ9 content between the B6, B6.Pdss2loxP/+, or B6.Pdss2loxP/loxP control mice (Panels A and B). Neither the B6.Podocin/cre,Pdss2loxP/loxP nor the B6.PEPCK/cre,Pdss2loxP/loxP mice had a significant reduction in the CoQ9 levels of total liver or kidney homogenates (Panels B and C), which is consistent with the fact that only a small subset of cells were affected by these targeted disruptions. However, the B6.Alb/cre,Pdss2loxP/loxP mice had less than 30 pmol CoQ9 per mg liver protein, which would be expected if most hepatic cells were affected by the albumin promoter-driven Cre expression.

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