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

Publication ,  Journal Article
Manoli, I; Sysol, JR; Li, L; Houillier, P; Garone, C; Wang, C; Zerfas, PM; Cusmano-Ozog, K; Young, S; Trivedi, NS; Cheng, J; Sloan, JL ...
Published in: Proc Natl Acad Sci U S A
August 13, 2013

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

August 13, 2013

Volume

110

Issue

33

Start / End Page

13552 / 13557

Location

United States

Related Subject Headings

  • Ubiquinone
  • Transgenes
  • Real-Time Polymerase Chain Reaction
  • Nephritis, Interstitial
  • Microscopy, Electron, Transmission
  • Microarray Analysis
  • Mice, Knockout
  • Mice
  • Methylmalonyl-CoA Mutase
  • Kidney Tubules, Proximal
 

Citation

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Manoli, I., Sysol, J. R., Li, L., Houillier, P., Garone, C., Wang, C., … Venditti, C. P. (2013). Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia. Proc Natl Acad Sci U S A, 110(33), 13552–13557. https://doi.org/10.1073/pnas.1302764110
Manoli, Irini, Justin R. Sysol, Lingli Li, Pascal Houillier, Caterina Garone, Cindy Wang, Patricia M. Zerfas, et al. “Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia.Proc Natl Acad Sci U S A 110, no. 33 (August 13, 2013): 13552–57. https://doi.org/10.1073/pnas.1302764110.
Manoli I, Sysol JR, Li L, Houillier P, Garone C, Wang C, et al. Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia. Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13552–7.
Manoli, Irini, et al. “Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia.Proc Natl Acad Sci U S A, vol. 110, no. 33, Aug. 2013, pp. 13552–57. Pubmed, doi:10.1073/pnas.1302764110.
Manoli I, 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. Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia. Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13552–13557.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

August 13, 2013

Volume

110

Issue

33

Start / End Page

13552 / 13557

Location

United States

Related Subject Headings

  • Ubiquinone
  • Transgenes
  • Real-Time Polymerase Chain Reaction
  • Nephritis, Interstitial
  • Microscopy, Electron, Transmission
  • Microarray Analysis
  • Mice, Knockout
  • Mice
  • Methylmalonyl-CoA Mutase
  • Kidney Tubules, Proximal