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

被引:50
作者
Miyata, Non [1 ]
Steffen, Janos [1 ]
Johnson, Meghan E. [1 ]
Fargue, Sonia [4 ]
Danpure, Christopher J. [4 ]
Koehler, Carla M. [1 ,2 ,3 ]
机构
[1] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA
[4] UCL, Dept Cell & Dev Biol, Div Biosci, London WC1E 6BT, England
基金
美国国家卫生研究院;
关键词
ALANINE-GLYOXYLATE AMINOTRANSFERASE; SMALL-MOLECULE INHIBITOR; STAGE RENAL-DISEASE; PROTEIN TRANSLOCATION; YEAST MITOCHONDRIA; TYPE-1; IMPORT; GENE; MUTATIONS; EVOLUTION;
D O I
10.1073/pnas.1408401111
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Primary hyperoxaluria 1 (PH1; Online Mendelian Inheritance in Man no. 259900), a typically lethal biochemical disorder, may be caused by the AGT(P11LG170R) 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 AGT(P11LG170R) 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 AGT(P11LG170R). Indeed, treatment with DECA inhibited AGT(P11LG170R) 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 AGT(P11LG170R) import into mitochondria, AGT(P11LG170R) 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.
引用
收藏
页码:14406 / 14411
页数:6
相关论文
共 30 条
[1]   End-stage renal disease in Kuwaiti children: An 8-year experience [J].
Al-Eisa, AA ;
Samhan, M ;
Naseef, M .
TRANSPLANTATION PROCEEDINGS, 2004, 36 (06) :1788-1791
[2]  
Behnam JI, 2006, BIOCHEM J, V394, P409, DOI 10.1042/BJ20051397
[3]   A third of the yeast mitochondrial proteome is dual localized: A question of evolution [J].
Ben-Menachem, Reut ;
Tal, Merav ;
Shadur, Tanya ;
Pines, Ophry .
PROTEOMICS, 2011, 11 (23) :4468-4476
[4]   Primary hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment [J].
Cochat, Pierre ;
Hulton, Sally-Anne ;
Acquaviva, Cecile ;
Danpure, Christopher J. ;
Daudon, Michel ;
De Marchi, Mario ;
Fargue, Sonia ;
Groothoff, Jaap ;
Harambat, Jerome ;
Hoppe, Bernd ;
Jamieson, Neville V. ;
Kemper, Markus J. ;
Mandrile, Giorgia ;
Marangella, Martino ;
Picca, Stefano ;
Rumsby, Gill ;
Salido, Eduardo ;
Straub, Michael ;
van Woerden, Christiaan S. .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 2012, 27 (05) :1729-1736
[5]   New Horizons for Old Drugs and Drug Leads [J].
Cragg, Gordon M. ;
Grothaus, Paul G. ;
Newman, David J. .
JOURNAL OF NATURAL PRODUCTS, 2014, 77 (03) :703-723
[6]   A Small Molecule Inhibitor of Redox-Regulated Protein Translocation into Mitochondria [J].
Dabir, Deepa V. ;
Hasson, Samuel A. ;
Setoguchi, Kiyoko ;
Johnson, Meghan E. ;
Wongkongkathep, Piriya ;
Douglas, Colin J. ;
Zimmerman, Johannes ;
Damoiseaux, Robert ;
Teitell, Michael A. ;
Koehler, Carla M. .
DEVELOPMENTAL CELL, 2013, 25 (01) :81-92
[7]   Primary hyperoxaluria type 1: AGT mistargeting highlights the fundamental differences between the peroxisomal and mitochondrial protein import pathways [J].
Danpure, Christopher J. .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2006, 1763 (12) :1776-1784
[8]   Variable peroxisomal and mitochondrial targeting of alanine: Glyoxylate aminotransferase in mammalian evolution and disease [J].
Danpure, CJ .
BIOESSAYS, 1997, 19 (04) :317-326
[9]  
DANPURE CJ, 1987, LANCET, V1, P289
[10]   Targeting of alanine: Glyoxylate aminotransferase in normal individuals and its mistargeting in patients with primary hyperoxaluria type 1 [J].
Danpure, CJ ;
Jennings, PR ;
Leiper, JM ;
Lumb, MJ ;
Oatey, PB .
PEROXISOMES: BIOLOGY AND ROLE IN TOXICOLOGY AND DISEASE, 1996, 804 :477-490