Pharmacologic rescue of an enzyme-trafficking defect in primary hyperoxaluria 1

Non Miyata, Janos Steffen, Meghan E. Johnson, Sonia Fargue, Christopher J. Danpure, Carla M. Koehler

研究成果: ジャーナルへの寄稿記事

29 引用 (Scopus)

抄録

Primary hyperoxaluria 1 (PH1; Online Mendelian Inheritance in Man no. 259900), a typically lethal biochemical disorder, may be caused by the AGTP11LG170R allele in which the alanine:glyoxylate aminotransferase (AGT) enzyme is mistargeted from peroxisomes to mitochondria. AGT contains a C-terminal peroxisomal targeting sequence, but mutations generate an N-terminal mitochondrial targeting sequence that directs AGT from peroxisomes to mitochondria. Although AGTP11LG170R is functional, the enzyme must be in the peroxisome to detoxify glyoxylate by conversion to alanine; in disease, amassed glyoxylate in the peroxisome is transported to the cytosol and converted to oxalate by lactate dehydrogenase, leading to kidney failure. From a chemical genetic screen, we have identified small molecules that inhibit mitochondrial protein import. We tested whether one promising candidate. Food and Drug Administration (FDA)-approved dequalinium chloride (DECA), could restore proper peroxisomal trafficking of AGTP11LG170R. Indeed treatment with DECA inhibited AGTP11LG170R translocation into mitochondria and subsequently restored trafficking to peroxisomes. Previous studies have suggested that a mitochondrial uncoupler might work in a similar manner. Although the uncoupler carbonyl cyanide m-chlorophenyl hydrazone inhibited AGTP11LG170R import into mitochondria, AGTP11LG170R aggregated in the cytosol, and cells subsequently died. In a cellular model system that recapitulated oxalate accumulation, exposure to DECA reduced oxalate accumulation, similar to pyridoxine treatment that works in a small subset of PH1 patients. Moreover, treatment with both DECA and pyridoxine was additive in reducing oxalate levels. Thus, repurposing the FDA-approved DECA may be a pharmacologic strategy to treat PH1 patients with mutations in AGT because an additional 75 missense mutations in AGT may also result in mistrafficking.

元の言語英語
ページ(範囲)14406-14411
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
111
発行部数40
DOI
出版物ステータス出版済み - 10 7 2014

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Peroxisomes
Oxalates
Mitochondria
Enzymes
Pyridoxine
United States Food and Drug Administration
Cytosol
Dequalinium
Carbonyl Cyanide m-Chlorophenyl Hydrazone
Genetic Databases
Mutation
Mitochondrial Proteins
Missense Mutation
L-Lactate Dehydrogenase
Alanine
Renal Insufficiency
Therapeutics
Alleles
Primary hyperoxaluria type 1
Alanine-glyoxylate transaminase

All Science Journal Classification (ASJC) codes

  • General

これを引用

Pharmacologic rescue of an enzyme-trafficking defect in primary hyperoxaluria 1. / Miyata, Non; Steffen, Janos; Johnson, Meghan E.; Fargue, Sonia; Danpure, Christopher J.; Koehler, Carla M.

:: Proceedings of the National Academy of Sciences of the United States of America, 巻 111, 番号 40, 07.10.2014, p. 14406-14411.

研究成果: ジャーナルへの寄稿記事

Miyata, Non ; Steffen, Janos ; Johnson, Meghan E. ; Fargue, Sonia ; Danpure, Christopher J. ; Koehler, Carla M. / Pharmacologic rescue of an enzyme-trafficking defect in primary hyperoxaluria 1. :: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; 巻 111, 番号 40. pp. 14406-14411.
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abstract = "Primary hyperoxaluria 1 (PH1; Online Mendelian Inheritance in Man no. 259900), a typically lethal biochemical disorder, may be caused by the AGTP11LG170R allele in which the alanine:glyoxylate aminotransferase (AGT) enzyme is mistargeted from peroxisomes to mitochondria. AGT contains a C-terminal peroxisomal targeting sequence, but mutations generate an N-terminal mitochondrial targeting sequence that directs AGT from peroxisomes to mitochondria. Although AGTP11LG170R is functional, the enzyme must be in the peroxisome to detoxify glyoxylate by conversion to alanine; in disease, amassed glyoxylate in the peroxisome is transported to the cytosol and converted to oxalate by lactate dehydrogenase, leading to kidney failure. From a chemical genetic screen, we have identified small molecules that inhibit mitochondrial protein import. We tested whether one promising candidate. Food and Drug Administration (FDA)-approved dequalinium chloride (DECA), could restore proper peroxisomal trafficking of AGTP11LG170R. Indeed treatment with DECA inhibited AGTP11LG170R translocation into mitochondria and subsequently restored trafficking to peroxisomes. Previous studies have suggested that a mitochondrial uncoupler might work in a similar manner. Although the uncoupler carbonyl cyanide m-chlorophenyl hydrazone inhibited AGTP11LG170R import into mitochondria, AGTP11LG170R aggregated in the cytosol, and cells subsequently died. In a cellular model system that recapitulated oxalate accumulation, exposure to DECA reduced oxalate accumulation, similar to pyridoxine treatment that works in a small subset of PH1 patients. Moreover, treatment with both DECA and pyridoxine was additive in reducing oxalate levels. Thus, repurposing the FDA-approved DECA may be a pharmacologic strategy to treat PH1 patients with mutations in AGT because an additional 75 missense mutations in AGT may also result in mistrafficking.",
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