Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Manoli, I., Sysol, J. R., Li, L., Houillier, P., Garone, C., Wang, C., Zerfas, P. M., Cusmano-Ozog, K., Young, S., Trivedi, N. S., Cheng, J., Sloan, J. L., Chandler, R. J., Abu-Asab, M., Tsokos, M., Elkahloun, A. G., Rosen, S., Enns, G. M., Berry, G. T., Hoffmann, V., DiMauro, S., Schnermann, J., Venditti, C. P. 2013; 110 (33): 13552-13557


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 ( 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.

View details for DOI 10.1073/pnas.1302764110

View details for Web of Science ID 000323069200075

View details for PubMedID 23898205

View details for PubMedCentralID PMC3746875