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Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia.

Proc Natl Acad Sci U S A, 2013/8/13;110(33):13552-7.

Manoli I[1], Sysol JR, Li L, Houillier P, Garone C, Wang C, Zerfas PM, Cusmano-Ozog K, Young S, Trivedi NS, Cheng J, Sloan JL, Chandler RJ, Abu-Asab M, Tsokos M, Elkahloun AG, Rosen S, Enns GM, Berry GT, Hoffmann V, DiMauro S, Schnermann J, Venditti CP

Affiliations

PMID: 23898205DOI: 10.1073/pnas.1302764110

Impact factor: 12.779

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.

Keywords: chronic renal failure; cobalamin; megamitochondria; organic acidemia

MeSH terms
Amino Acid Metabolism, Inborn Errors; Animals; Antioxidants; Biomarkers; Blotting, Western; DNA Primers; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fluorescein-5-isothiocyanate; Genotype; Glomerular Filtration Rate; Humans; Immunohistochemistry; Kidney Tubules, Proximal; Methylmalonyl-CoA Mutase; Mice; Mice, Knockout; Microarray Analysis; Microscopy, Electron, Transmission; Nephritis, Interstitial; Real-Time Polymerase Chain Reaction; Transgenes; Ubiquinone
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