title: Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia.
abstract: Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut(-/-) mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut(-/-);Tg(INS-Alb-Mut) mice, although completely rescued from neonatal lethality that was displayed by Mut(-/-) mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut(-/-);Tg(INS-Alb-Mut) kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut(-/-);Tg(INS-Alb-Mut) mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Irini
authors.initials: I
authors.lastname: Manoli
authors.forename: Justin R
authors.initials: JR
authors.lastname: Sysol
authors.forename: Lingli
authors.initials: L
authors.lastname: Li
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.forename: Caterina
authors.initials: C
authors.lastname: Garone
authors.forename: Cindy
authors.initials: C
authors.lastname: Wang
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Zerfas
authors.forename: Kristina
authors.initials: K
authors.lastname: Cusmano-Ozog
authors.forename: Sarah
authors.initials: S
authors.lastname: Young
authors.forename: Niraj S
authors.initials: NS
authors.lastname: Trivedi
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sloan
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Chandler
authors.forename: Mones
authors.initials: M
authors.lastname: Abu-Asab
authors.forename: Maria
authors.initials: M
authors.lastname: Tsokos
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.forename: Seymour
authors.initials: S
authors.lastname: Rosen
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Enns
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Berry
authors.forename: Victoria
authors.initials: V
authors.lastname: Hoffmann
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
authors.forename: Jurgen
authors.initials: J
authors.lastname: Schnermann
authors.forename: Charles P
authors.initials: CP
authors.lastname: Venditti
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D016650:Fluorescein-5-isothiocyanate; D005838:Genotype; D005919:Glomerular Filtration Rate / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000503:physiopathology*; D008765:Methylmalonyl-CoA Mutase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D046529:Microscopy, Electron, Transmission; D009395:Nephritis, Interstitial / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D019076:Transgenes / Q000235:genetics; D014451:Ubiquinone / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D017931:DNA Primers; D014451:Ubiquinone; D008765:Methylmalonyl-CoA Mutase; D016650:Fluorescein-5-isothiocyanate
keywords: chronic renal failure; cobalamin; megamitochondria; organic acidemia
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