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Novel Insights Into the Pathophysiology of Kidney Disease in Methylmalonic Aciduria

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Novel Insights Into the Pathophysiology of Kidney Disease in Methylmalonic Aciduria Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2017 Novel Insights into the Pathophysiology of Kidney Disease in Methylmalonic Aciduria Schumann, Anke Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-148531 Dissertation Published Version Originally published at: Schumann, Anke. Novel Insights into the Pathophysiology of Kidney Disease in Methylmalonic Aciduria. 2017, University of Zurich, Faculty of Medicine. Novel Insights into the Pathophysiology of Kidney Disease in Methylmalonic Aciduria Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Anke Schumann aus Deutschland Promotionskommission Prof. Dr. Olivier Devuyst (Vorsitz und Leitung der Dissertation) Prof. Dr. Matthias R. Baumgartner Prof. Dr. Stefan Kölker Zürich, 2017 DECLARATION I hereby declare that the presented work and results are the product of my own work. Contributions of others or sources used for explanations are acknowledged and cited as such. This work was carried out in Zurich under the supervision of Prof. Dr. O. Devuyst and Prof. Dr. M.R. Baumgartner from August 2012 to August 2016. Peer-reviewed publications presented in this work: Haarmann A, Mayr M, Kölker S, Baumgartner ER, Schnierda J, Hopfer H, Devuyst O, Baumgartner MR. Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up. Mol Genet Metab. 2013 Dec;110(4):472-6. doi: 10.1016/j.ymgme.2013.08.021. Epub 2013 Sep 17. Schumann A, Luciani A, Berquez M, Tokonami N, Debaix H, Forny P, Kölker S, Diomedi Camassei F, CB, MK, Faresse N, Hall A, Ziegler U, Baumgartner M and Devuyst O. Impaired mitophagy links mitochondrial dysfunction and epithelial cell damage in methylmalonic aciduria. In preparation. Peer-reviewed publications associated with the thesis: Devuyst O, Schumann A. Peritoneal dialysis: nanoparticles have entered the game. V. Perit Dial Int. 2015 May-Jun;35(3):240. doi: 10.3747/pdi.2015.00075. Ruppert T, Schumann A, Gröne HJ, Okun JG, Kölker S, Morath MA, Sauer SW. Molecular and biochemical alterations in tubular epithelial cells of patients with isolated methylmalonic aciduria. Hum Mol Genet. 2015 Dec 15;24(24):7049-59. doi: 10.1093/hmg/ddv405. Epub 2015 Sep 29. Forny P, Schumann A, Mustedanagic M, Mathis D, Wulf MA, Nägele N, Langhans CD, Zhakupova A, Heeren J, Scheja L, Fingerhut R, Peters HL, Hornemann T, Thony B, Kölker S, Burda P, Froese DS, Devuyst O, Baumgartner MR. Novel Mouse Models of Methylmalonic Aciduria Recapitulate Phenotypic Traits with a Genetic Dosage Effect. J Biol Chem. 2016 Sep 23;291(39):20563-73. doi: 10.1074/jbc.M116.747717. 1 This thesis is dedicated to everyone who supported me on my way. 2 TABLE OF CONTENTS LIST OF ABBREVIATIONS 5 ABSTRACT IN ENGLISH 7 ABSTRACT IN GERMAN 9 I. INTRODUCTION 11 I.1 Inborn errors of metabolism 11 I.1.1 Rare diseases 11 I.1.2 Classification of inborn errors of metabolism 11 I.1.2.1 Presentation of inborn errors of metabolism 12 I.2 Disorders of branched chain amino acid metabolism 14 I.2.1 Organic acidurias 14 I.2.1.1 Presentation of organic acidurias 15 I.2.1.2 Diagnosis of organic acidurias 16 I.2.1.3 Current opinion on alterations in metabolic flux in organic acidurias 17 I.2.1.4 General treatment principles of organic acidurias 18 I.2.2 Isolated and combined forms of methylmalonic aciduria 18 I.2.2.1 Isolated MMA 18 I.2.2.2 Combined forms of MMA 19 I.2.2.3 Clinical presentation of isolated MMA 20 I.2.2.4 Diagnostic testing in MMA 21 I.2.2.5 Treatment options in isolated MMA 22 I.2.2.6 Pathophysiology of kidney disease in MMA 23 I.3 Impact of mitochondrial function on human health and disease 24 I.3.1 Mitochondrial energy metabolism 24 I.3.1.1 Disorders in mitochondrial energy metabolism 25 I.3.1.2 Mitochondrial dynamics and homeostasis 25 I.3.1.3 Mitochondrial dysfunction in renal disease 27 3 I.3.2 Autophagy and mitophagy 29 I.3.2.1 The role of autophagy in kidney disease 32 II. AIMS OF THE THESIS 34 II.1 Characterization of the classical disease course and possible influence of adenosylcobalamin (vitamin B12) on the progression of CKD in methylmalonic aciduria (MMA) II.2 Mechanistic studies in the different mouse and human models reveal mitochon- drial dysfunction and impaired autophagy to drive kidney damage in methylmalonic aciduria III. Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up 36 IV. Impaired Mitophagy Links Mitochondrial Dysfunction and Epithelial Cell Damage in Methylmalonic Aciduria 52 V. DISCUSSION AND PERSPECTIVES 102 VI. REFERENCES 112 VII. CURRICULUM VITAE 129 4 LIST OF ABBREVIATIONS AdoCbl 5’-deoxyadenosylcobalamin, Adenosylcobalamin ATP Adenosine Triphosphate BfnAI Bafilomycin BCAA Branched chain amino acids BCKD Branched chain 2-ketoacid dehydrogenase complex cbl Cobalamin CKD Chronic kidney disease CoA Acyl coenzyme A C3 Propionyl carnitine CoQ10 Coenzyme Q10 CtsD Cathepsin D DT Distal tubule DNA Desoxyribonucleic aid GC-MS Gas chromatography mass spectometry GFR Glomerular filtration rate IEM Inborn errors of metabolism IMM Inner mitochondrial membrane IMS Intermembrane space IVA Isovaleric aciduria KIM-1 Kidney injury molecule-1 LCN2 Lipocalin 2 Mitoquinone MitoQ MQC Mitochondrial quality control MMA Methylmalonic aciduria MMP Mitochondrial membrane potential mPTC Mouse proximal tubule cells mROS Mitochondrial reactive oxygen species MS Methionine synthase 5 MS/MS Tandem mass spectometry mtDNA Mitochondrial DNA MSUD Maple sirup urine disease MT MitoTEMPO MUT Methylmalonyl-CoA mutase Mut(-) residual enzyme activity of MUT Mut(0) no residual enzyme activity of MUT OA Organic aciduria OMM Outer mitochondrial membrane PA Propionic aciduria PT Proximal tubule PGC-1-α Peroxisome proliferator-activated receptor-gamma coactivator-alpha ROS Reactive oxygen species TAL Thick ascending limb TCA Tricarboxylic acid cycle (=Krebs-cycle) TGF- Transforming growth factor-beta 6 ABSTRACT IN ENGLISH Disturbances in mitochondrial energy metabolism lead to severe effects on human health. To fulfill their important functions, mitochondria are organized in an interconnected network, providing energy and biosynthetic intermediates necessary for cellular homoeostasis and tissue function. Methylmalonic aciduria (MMA) is a rare inborn error of metabolism due to the mutation of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT) catalyzing the conversion of methylmalonyl-CoA to succinyl-CoA requiring vitamin B12 as an essential co-factor. The reaction fuels metabolites from the break-down of branched chain amino acids, odd chain fatty acids, cholesterol and propionic acid into the Krebs cycle (TCA). Mutations in the recessively inherited MUT-gene lead to a partial mut(-) or complete mut(0) loss of MUT function. MMA clinically results in severe metabolic acidosis due to accumulation of organic acids (predominantly methylmalonic acid), hyper-ammonaemia and an acute, life-threatening metabolic crisis usually manifesting in the neonatal period. MUT is expressed in all tissue organs; high expression levels are found in the kidney, where mitochondria provide energy for transport processes mediated by renal tubular cells. Renal tubular dysfunction and chronic kidney disease (CKD) due to tubulo-interstitial lesions are the main long-term consequence in MMA patients. The pathomechanisms linking mitochondrial enzyme deficiency to renal epithelial dysfunction in basically all MMA patients remains largely unknown. Onset and progression of CKD seems to be linked to the severity of the mutation and is most pronounced in mut(0) patients, showing the highest levels of methylmalonic acid. Main hypothesis for CKD in MMA are abnormal mitochondrial function due to energetic depletion of the TCA, oxidative stress and potentially toxic effects of accumulating methylmalonic acid. On top of suffering from a life-threatening disease, CKD imposes a high morbidity and mortality risk on MMA patients. The identification of kidney-protective measures and the in-depth understanding of the underlying pathomechanisms inducing CKD is crucial to slow down or even prevent severe kidney damage in a next step. Therefore, the aim of the thesis was to 1) investigate the stabilizing effect of co- factor application for renal protection in a mildly affected MMA patient and 2) to provide a (potentially targetable) link between MUT deficiency, mitochondrial dysfunction and renal epithelial cell damage in different in vitro and in vivo models. The obtained data provide evidence, that even mild forms of MMA inevitably lead to CKD and underline the importance of early and adequate co-factor supplementation in vitamin B12-responsive MMA patients. Maintenance of mitochondrial integrity is a key requirement to preserve cellular homeostasis and function particularly in highly specialized renal epithelial cells. Using different MMA-models we provide evidence, that MUT deficiency leads to severe disturbance of the mitochondrial network in terms of morphology, function and homeostasis. Dysregulation of the 7 organelle-specific mitochondrial quality control (MQC) system initiated by PINK1 and parkin induces impaired autophagy-mediated clearance of dysfunctional mitochondria. As a consequence, the cells accumulate autophagic proteins and mitochondrial reactive oxygen species potentiating cellular and tissue damage. Mitochondria-targeted
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