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: Irini Manoli, Justin R Sysol, Lingli Li, Pascal Houillier, Caterina Garone, Cindy Wang, Patricia M Zerfas, Kristina Cusmano-Ozog, Sarah Young, Niraj S Trivedi, Jun Cheng, Jennifer L Sloan, Randy J Chandler, Mones Abu-Asab, Maria Tsokos, Abdel G Elkahloun, Seymour Rosen, Gregory M Enns, Gerard T Berry, Victoria Hoffmann, Salvatore DiMauro, Jurgen Schnermann, Charles P Venditti
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 33 Pg. 13552-7 (Aug 13 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23898205 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Biomarkers
• DNA Primers
• Ubiquinone
• Methylmalonyl-CoA Mutase
• Fluorescein-5-isothiocyanate

Topics

• Amino Acid Metabolism, Inborn Errors (drug therapy, enzymology, pathology)
• Animals
• Antioxidants (pharmacology, therapeutic use)
• Biomarkers (metabolism)
• Blotting, Western
• DNA Primers (genetics)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Fluorescein-5-isothiocyanate
• Genotype
• Glomerular Filtration Rate (genetics)
• Humans
• Immunohistochemistry
• Kidney Tubules, Proximal (physiopathology)
• Methylmalonyl-CoA Mutase (deficiency, genetics, metabolism)
• Mice
• Mice, Knockout
• Microarray Analysis
• Microscopy, Electron, Transmission
• Nephritis, Interstitial (genetics)
• Real-Time Polymerase Chain Reaction
• Transgenes (genetics)
• Ubiquinone (pharmacology)