Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia
- 29 July 2013
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 110 (33), 13552-13557
- https://doi.org/10.1073/pnas.1302764110
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−/−;TgINS-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−/−;TgINS-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−/−;TgINS-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.This publication has 33 references indexed in Scilit:
- Variable dietary management of methylmalonic acidemia: metabolic and energetic correlationsThe American Journal of Clinical Nutrition, 2011
- Lipocalin 2 is essential for chronic kidney disease progression in mice and humansJCI Insight, 2010
- Liver-Directed Recombinant Adeno-Associated Viral Gene Delivery Rescues a Lethal Mouse Model of Methylmalonic Acidemia and Provides Long-Term Phenotypic CorrectionHuman Gene Therapy, 2010
- Optic neuropathy in methylmalonic acidemia: the role of neuroprotectionJournal of Inherited Metabolic Disease, 2010
- Long-term Rescue of a Lethal Murine Model of Methylmalonic Acidemia Using Adeno associated Viral Gene TherapyMolecular Therapy, 2010
- Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemiaProceedings of the National Academy of Sciences of the United States of America, 2009
- Mitochondrial dysfunction inmutmethylmalonic acidemiaThe FASEB Journal, 2008
- Primary Coenzyme Q Deficiency in Pdss2 Mutant Mice Causes Isolated Renal DiseasePLoS Genetics, 2008
- Adenovirus-Mediated Gene Delivery Rescues a Neonatal Lethal Murine Model of mut0 Methylmalonic AcidemiaHuman Gene Therapy, 2008
- Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscleBMC Medical Genetics, 2007