Focal segmental glomerulosclerosis is associated with a<i>PDSS2</i>haplotype and, independently, with a decreased content of coenzyme Q<sub>10</sub>

Gasser, David L.; Winkler, Cheryl A.; Peng, Min; An, Ping; McKenzie, Louise A.; Kirk, Gregory D.; Shi, Yuchen; Xie, Letian X.; Marbois, Beth N.; Clarke, Catherine F.; Kopp, Jeffrey B.

doi:10.1152/ajprenal.00143.2013

Cited by 40 publications

(28 citation statements)

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“…Should these findings extend beyond E. coli to other species and possibly other membrane-related stresses, it might be a promising approach to target stress-induced ubiquinone accumulation for the treatment of infectious and other diseases. For instance, recent studies have found that human patients suffering from nephrotic syndrome displayed reduced Q10 levels 42 , and a mutation in a Q10 biosynthetic enzyme in mice caused pathological symptoms similar to Parkinson's disease 43 . Finally, induction of Q8 accumulation by elevated salt levels might be an effective strategy for the biotechnological production of this or related compounds 44 .…”

Section: Discussionmentioning

confidence: 99%

Ubiquinone accumulation improves osmotic-stress tolerance in Escherichia coli

2014

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Bacteria are thought to cope with fluctuating environmental solute concentrations primarily by adjusting the osmolality of their cytoplasm. To obtain insights into underlying metabolic adaptions, we analyzed the global metabolic response of Escherichia coli to sustained hyperosmotic stress using non-targeted mass spectrometry. We observed that 52% of 1,071 detected metabolites, including known osmoprotectants, changed abundance with increasing salt challenge. Unexpectedly, unsupervised data analysis revealed a substantial increase of most intermediates in the ubiquinone-8 (Q8) biosynthesis pathway and a 110-fold accumulation of Q8 itself, as confirmed by quantitative lipidomics. We then demonstrate that Q8 is necessary for acute and sustained osmotic stress tolerance using Q8 mutants and tolerance rescue through feeding non-respiratory Q8 analogues. Finally, in vitro experiments with artificial liposomes reveal mechanical membrane stabilization as a principal mechanism of Q8-mediated osmoprotection. Thus, we find that besides regulating intracellular osmolality, E. coli enhances its cytoplasmic membrane stability to withstand osmotic stress. AbstractBacteria are thought to cope with fluctuating environmental solute concentrations primarily by adjusting the osmolality of their cytoplasm. To obtain insights into underlying metabolic adaptions, we analyzed the global metabolic response of Escherichia coli to sustained hyperosmotic stress using non-targeted mass spectrometry. We observed that 52% of 1,071 detected metabolites, including known osmoprotectants, changed abundance with increasing salt challenge. Unexpectedly, unsupervised data analysis revealed a substantial increase of most intermediates in the ubiquinone-8 (Q8) biosynthesis pathway and a 110-fold accumulation of Q8 itself, as confirmed by quantitative lipidomics. We then demonstrate that Q8 is necessary for acute and sustained osmotic stress tolerance using Q8 mutants and tolerance rescue through feeding non-respiratory Q8 analogues.Finally, in vitro experiments with artificial liposomes reveal mechanical membrane stabilization as a principal mechanism of Q8-mediated osmoprotection. Thus, we find that besides regulating intracellular osmolality, E. coli enhances its cytoplasmic membrane stability to withstand osmotic stress.

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Section: Discussionmentioning

confidence: 99%

Ubiquinone accumulation improves osmotic-stress tolerance in Escherichia coli

2014

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“…The RP-HPLC-MS/MS analyses were performed as previously described for determination of Q 6 in yeast lipid extracts ( 11,18 ) and determination of Q 9 and Q 10 in mammalian lipid extracts ( 28,29 ). Briefl y, a 4000 QTRAP linear MS/MS spectrometer from Applied Biosystems (Foster City, CA) was used.…”

Section: Rp-hplc-ms/msmentioning

confidence: 99%

Resveratrol and para-coumarate serve as ring precursors for coenzyme Q biosynthesis

Xie

Williams

et al. 2015

Journal of Lipid Research

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“…A haplotype defined by two noncoding single-nucleotide polymorphisms in the PDSS2 gene was identified at an increased frequency in European American populations with FSGS, but not African American populations with FSGS. 58 Another interesting observation was that lymphoblastoid cell lines derived from individuals with FSGS had decreased coenzyme Q 10 content compared to cell lines from control populations without kidney disease, but this did not correlate with the PDSS2 haplotype. These results suggest that proteinuric kidney disease may contribute to a secondary form of coenzyme Q 10 deficiency that may occur through epigenetic mechanisms.…”

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confidence: 99%

Renal manifestations of genetic mitochondrial disease

O’Toole¹

2014

IJNRD

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Mitochondrial diseases can be related to mutations in either the nuclear or mitochondrial genome. Childhood presentations are commonly associated with renal tubular dysfunction, but renal involvement is less commonly reported outside of this age-group. Mitochondrial diseases are notable for the significant variability in their clinical presentation and the broad spectrum of genes implicated in their etiology. These features contribute to the challenges of establishing a definitive diagnosis and understanding the pathogenetic mechanisms leading to kidney involvement in these diseases. Here, we review the deoxyribonucleic acid variants in the mitochondrial and nuclear genomes that have been associated with a kidney phenotype, and examine some of the possible pathogenic mechanisms that may contribute to the expression of a renal phenotype.

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Focal segmental glomerulosclerosis is associated with aPDSS2haplotype and, independently, with a decreased content of coenzyme Q₁₀

Abstract: JB. Focal segmental glomerulosclerosis is associated with a PDSS2 haplotype and, independently, with a decreased content of coenzyme Q 10.

Cited by 40 publications

References 68 publications

Ubiquinone accumulation improves osmotic-stress tolerance in Escherichia coli

Ubiquinone accumulation improves osmotic-stress tolerance in Escherichia coli

Resveratrol and para-coumarate serve as ring precursors for coenzyme Q biosynthesis

Renal manifestations of genetic mitochondrial disease

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Focal segmental glomerulosclerosis is associated with aPDSS2haplotype and, independently, with a decreased content of coenzyme Q10

Abstract: JB. Focal segmental glomerulosclerosis is associated with a PDSS2 haplotype and, independently, with a decreased content of coenzyme Q 10.

Cited by 40 publications

References 68 publications

Ubiquinone accumulation improves osmotic-stress tolerance in Escherichia coli

Ubiquinone accumulation improves osmotic-stress tolerance in Escherichia coli

Resveratrol and para-coumarate serve as ring precursors for coenzyme Q biosynthesis

Renal manifestations of genetic mitochondrial disease

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Focal segmental glomerulosclerosis is associated with aPDSS2haplotype and, independently, with a decreased content of coenzyme Q₁₀