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Targeting Proximal Tubule Mitochondrial Dysfunction Attenuates the Renal Disease of Methylmalonic Acidemia

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Targeting Proximal Tubule Mitochondrial Dysfunction Attenuates the Renal Disease of Methylmalonic Acidemia Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia Irini Manolia,1, Justin R. Sysola,1, Lingli Lib, Pascal Houillierb,c, Caterina Garoned,e, Cindy Wanga, Patricia M. Zerfasf, Kristina Cusmano-Ozogg, Sarah Youngh, Niraj S. Trivedii, Jun Chengj, Jennifer L. Sloana, Randy J. Chandlera, Mones Abu-Asabk, Maria Tsokosk, Abdel G. Elkahlounl, Seymour Rosenm,n, Gregory M. Ennsg, Gerard T. Berryo, Victoria Hoffmannf, Salvatore DiMaurod, Jurgen Schnermannb, and Charles P. Vendittia,2 aGenetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892; bKidney Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20814; cInstitut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 872, Department of Physiology, Georges Pompidou European Hospital, Assistance Publique–Hôpitaux de Paris, Paris Descartes University, 75015 Paris, France; dColumbia University Medical Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032; eHuman Genetics Joint PhD Program, University of Bologna and Turin, 10126 Turin, Italy; fOffice of Research Services, Division of Veterinary Resources, NIH, Bethesda, MD 20892; gDivision of Medical Genetics, Stanford University, Stanford, CA 94305; hBiochemical Genetics Laboratory, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27713; iGenome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892; jEmbryonic Stem Cell and Transgenic Mouse Core Facility, National Human Genome Research Institute, NIH, Bethesda, MD 20892; kUltrastructural Pathology Section, Center for Cancer Research, NIH, Bethesda, MD 20892; lCancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892; mDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215; and nDepartment of Pathology and oManton Center for Orphan Disease Research, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115 Edited by Arthur L. Beaudet, Baylor College of Medicine, Houston, TX, and approved July 3, 2013 (received for review February 12, 2013) Isolated methylmalonic acidemia (MMA), caused by deficiency of and symptomatic care, although liver, kidney, and combined the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is liver–kidney transplantation have been used in the severely af- often complicated by end stage renal disease that is resistant to fected patients (3). Kidney disease in MMA can manifest with conventional therapies, including liver transplantation. To estab- proximal and/or distal tubular dysfunction and is associated with lish a viable model of MMA renal disease, Mut was expressed in progressive tubulointerstitial disease (1, 4), eventually leading to MEDICAL SCIENCES − − the liver of Mut / mice as a stable transgene under the control of ESRD in >50% of those with severe forms of MMA by the age − − Mut an albumin (INS-Alb-Mut) promoter. Mut / ;TgINS-Alb- mice, al- of 8 y (5). Although renal disease can be present as early as 18 mo though completely rescued from neonatal lethality that was dis- (6), the decreased muscle mass seen in the patients (1, 7) renders − − played by Mut / mice, manifested a decreased glomerular filtration routine laboratory markers, such as creatinine, poorly predictive rate (GFR), chronic tubulointerstitial nephritis and ultrastructural of kidney involvement early in disease evolution. changes in the proximal tubule mitochondria associated with ab- Patients with MMA who have been treated by orthotopic liver errant tubular function, as demonstrated by single-nephron GFR transplantation display metabolic stability yet develop extrahe- −/− INS-Alb-Mut studies. Microarray analysis of Mut ;Tg kidneys identi- patic disease, including ESRD, and, therefore, provide a clinical fied numerous biomarkers, including lipocalin-2, which was then paradigm for the development of animal models to study the used to monitor the response of the GFR to antioxidant therapy in renal pathophysiology of MMA (8). In the present work, we have − − the mouse model. Renal biopsies and biomarker analysis from a large used transgenesis to create Mut / mice that express Mut in and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) hepatocytes under the control of the mouse albumin promoter −/− − − precisely replicated the findings in the animals, establishing Mut ; (Mut / ;TgINS-Alb-Mut). These mice are protected from the neo- INS-Alb-Mut − − Tg mice as a unique model of MMA renal disease. Our natal lethality that characterizes the Mut / mice (9, 10) but studies suggest proximal tubular mitochondrial dysfunction is a manifest CTIN and a decreased glomerular filtration rate (GFR) key pathogenic mechanism of MMA-associated kidney disease, iden- associated with megamitochondria formation (11) and decreased tify lipocalin-2 as a biomarker of increased oxidative stress in the cytochrome c oxidase (COX) activity in the proximal tubules. renal tubule, and demonstrate that antioxidants can attenuate the The murine studies prompted the search for similar pathology in renal disease of MMA. kidney biopsies from MMA patients and suggested a therapeutic approach directed at alleviating mitochondrial dysfunction. Ge- cobalamin | chronic renal failure | megamitochondria | organic acidemia nomic and biochemical characterization of disease progression in − − the Mut / ;TgINS-Alb-Mut mice identified >50 biomarkers associ- enal tubular dysfunction with progression into chronic tubu- ated with MMA renal disease, including lipocalin-2 (Lcn2), that Rlointerstitial nephritis (CTIN) and end stage renal disease (ESRD) is a cardinal manifestation of methylmalonic acidemia (MMA), a common and severe organic acidemia characterized Author contributions: I.M., J.S., and C.P.V. designed research; I.M., J.R.S., L.L., P.H., C.G., by metabolic instability, multisystemic complications, and high C.W., P.M.Z., S.Y., N.S.T., J.L.S., M.A.-A., M.T., A.G.E., J.S., and C.P.V. performed research; K.C.-O., J.C., R.J.C., S.R., G.M.E., G.T.B., and C.P.V. contributed new reagents/analytic tools; mortality (1, 2). Isolated MMA is primarily caused by mutations I.M., J.R.S., L.L., P.H., C.G., C.W., K.C.-O., S.Y., N.S.T., J.L.S., M.A.-A., M.T., A.G.E., S.R., G.M.E., in the vitamin B12-dependent, mitochondrial matrix-localized G.T.B., V.H., S.D., J.S., and C.P.V. analyzed data; and I.M., J.S., and C.P.V. wrote the paper. methylmalonyl-CoA mutase (MUT), an enzyme that mediates The authors declare no conflict of interest. the entry of carbon skeletons derived from branched-chain This article is a PNAS Direct Submission. amino acid, odd-chained fatty acid, and cholesterol oxidation Freely available online through the PNAS open access option. into the Krebs cycle (3). Although the MUT enzyme is expressed Data deposition: The data reported in this paper have been deposited in the Gene Ex- ubiquitously, the clinical features observed, such as pancreatitis, pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE41044). metabolic “stroke” of the globus pallidus, optic nerve atrophy, 1I.M. and J.R.S. contributed equally to this work. immune dysfunction, and especially renal disease, indicate a tis- 2To whom correspondence should be addressed. E-mail: [email protected]. fi sue-speci c vulnerability in this metabolic disorder. There are no This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. treatments available for MMA other than dietary management 1073/pnas.1302764110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1302764110 PNAS Early Edition | 1of6 Downloaded by guest on September 28, 2021 was subsequently validated in a large cohort of MMA patients. A and multiple matrix granules/deposits in the renal tubular cytosol of − − therapeutic regimen, directed at reducing oxidant injury with Mut / ;TgINS-Alb-Mut kidneys (Fig. S2A). CoQ10 and vitamin E (VitE), ameliorated the loss of GFR in the − − Mut / ;TgINS-Alb-Mut mice and was predicted by plasma Lcn2 Acceleration of MMA Renal Disease by Ingestion of a High-Protein Diet. concentrations. Our studies establish LCN2 as a biomarker of To recapitulate the renal disease observed in some patients post- oxidative stress and renal mitochondrial dysfunction and define liver transplantation with liberalized protein intake (8), the mice an approach for the treatment and monitoring of kidney disease were fed a high-protein (HP) (casein) chow. A dietary challenge = −/− INS-Alb-Mut in patients with MMA. study for 6 mo (n 8) was performed in female Mut ;Tg mice, because only rarely did male littermates survive beyond 2 mo − − Results of age on the same diet. On the HP chow, the Mut / ;TgINS-Alb-Mut − − Hepatic Expression of Mut Provides Phenotypic Attenuation in Mut / mice experienced a rapid weight loss of 14 ± 4% within the first Mice. A construct was engineered to express the Mut gene under month and failed to regain their weight (Fig. S3A). Plasma − − the control of the chimeric murine minimal albumin promoter methylmalonic acid concentration in the Mut / ;TgINS-Alb-Mut and α-fetoprotein enhancer (Fig. S1 A and B). Three trans- mice was 863 ± 288 μmol/L at baseline, 1,500 ± 620 μmol/L after mitting C57BL/6 TgINS-Alb-Mut founder lines were established and 2 mo, and 1,938 ± 418 μmol/L after 6 mo on a HP diet (P = 0.013 + − −/− INS-Alb-Mut crossed to C57BL/6 Mut / mice (9, 12). To accelerate the de- for Mut ;Tg mice compared with baseline values and velopment of extrahepatic manifestations, the lowest expressing P < 0.0001 compared with heterozygotes) (Fig. S3B). Studies in − − line was selected for further study. Mut / ;TgINS-Alb-Mut mice plasma vs. brain tissue extracts, obtained 2 mo after HP diet in were uniformly rescued from neonatal lethality (Fig. 1A) and a separate group of mice, showed significantly higher methyl- appeared comparable to their heterozygote littermates (Fig. 1B). malonic acid concentrations in the brain tissue compared with = = Immunoreactive Mut protein was detected only in the liver of the mice fed regular chow (RD) (Fig.
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