title: Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy.
abstract: We recently reported an autosomal dominant form of renal Fanconi syndrome caused by a missense mutation in the third codon of the peroxisomal protein EHHADH. The mutation mistargets EHHADH to mitochondria, thereby impairing mitochondrial energy production and, consequently, reabsorption of electrolytes and low-molecular-weight nutrients in the proximal tubule. Here, we further elucidate the molecular mechanism underlying this pathology. We find that mutated EHHADH is incorporated into mitochondrial trifunctional protein (MTP), thereby disturbing β-oxidation of long-chain fatty acids. The resulting MTP deficiency leads to a characteristic accumulation of hydroxyacyl- and acylcarnitines. Mutated EHHADH also limits respiratory complex I and corresponding supercomplex formation, leading to decreases in oxidative phosphorylation capacity, mitochondrial membrane potential maintenance, and ATP generation. Activity of the Na(+)/K(+)-ATPase is thereby diminished, ultimately decreasing the transport activity of the proximal tubule cells.
authors.affiliation: Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Assmann
authors.affiliation: Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Dettmer
authors.affiliation: Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Johann M B
authors.initials: JMB
authors.lastname: Simbuerger
authors.affiliation: Medical Cell Biology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Broeker
authors.affiliation: Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Nuernberger
authors.affiliation: Department of Hematology and Oncology, University Clinic Regensburg, 93053 Regensburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Renner
authors.affiliation: Centre for Nephrology, University College London, London NW3 2PF, UK.
authors.forename: Holly
authors.initials: H
authors.lastname: Courtneidge
authors.affiliation: Centre for Nephrology, University College London, London NW3 2PF, UK.
authors.forename: Enriko D
authors.initials: ED
authors.lastname: Klootwijk
authors.affiliation: Institute of Analytical Chemistry, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Duerkop
authors.affiliation: Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hall
authors.affiliation: Centre for Nephrology, University College London, London NW3 2PF, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.affiliation: Medical Cell Biology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Reichold
authors.affiliation: Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany. Electronic address: joerg.reinders@ukr.de.
authors.forename: Joerg
authors.initials: J
authors.lastname: Reinders
mesh_terms: D000818:Animals; D001692:Biological Transport; D002457:Cell Extracts; D004734:Energy Metabolism; D005198:Fanconi Syndrome / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D018374:LLC-PK1 Cells; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D063994:Peroxisomal Bifunctional Enzyme / Q000378:metabolism; D040901:Proteomics; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013552:Swine
chemical_list: D002457:Cell Extracts; D005227:Fatty Acids; D063994:Peroxisomal Bifunctional Enzyme; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Fanconi syndrome; fatty acid oxidation; mitochondriopathy; supercomplexes