Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy
| Autor: | Andrew M. Hall, Kathrin Renner, Markus Reichold, Nadine Assmann, Katja Dettmer, Carsten Broeker, Peter J. Oefner, Enriko Klootwijk, Nadine Nuernberger, Holly Courtneidge, Joerg Reinders, Johann M.B Simbuerger, Robert Kleta, Axel Duerkop |
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| Přispěvatelé: | University of Zurich, Reinders, Joerg |
| Rok vydání: | 2016 |
| Předmět: |
Cell Extracts
Proteomics 0301 basic medicine Mitochondrial Diseases 10017 Institute of Anatomy Swine 610 Medizin Mitochondrial trifunctional protein Mitochondrion Kidney environment and public health supercomplexes 0302 clinical medicine 570 Biowissenschaften Biologie Missense mutation lcsh:QH301-705.5 fatty acid oxidation ddc:610 Microscopy Confocal biology Reabsorption Fatty Acids Peroxisome Mitochondria Cell biology mitochondriopathy FATTY-ACID OXIDATION BETA-OXIDATION 3-HYDROXYACYL-COA DEHYDROGENASE TRIFUNCTIONAL PROTEIN PHOSPHORYLATION TUBULE CELLS COA ATP SPECIFICITY Biochemistry 030220 oncology & carcinogenesis Phosphorylation ddc:570 Sodium-Potassium-Exchanging ATPase Oxidation-Reduction Subcellular Fractions inorganic chemicals ddc:540 610 Medicine & health Genetics and Molecular Biology Oxidative phosphorylation macromolecular substances Peroxisomal Bifunctional Enzyme General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 1300 General Biochemistry Genetics and Molecular Biology medicine Animals Fanconi syndrome Biological Transport medicine.disease enzymes and coenzymes (carbohydrates) 030104 developmental biology lcsh:Biology (General) 540 Chemie Mutation General Biochemistry biology.protein LLC-PK1 Cells 570 Life sciences bacteria Energy Metabolism |
| Zdroj: | Cell Reports, Vol 15, Iss 7, Pp 1423-1429 (2016) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2016.04.037 |
| Popis: | Summary: 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. : Assmann et al. examine the molecular mechanism underlying a recently described Fanconi syndrome. Mistargeting of the peroxisomal protein EHHADH to mitochondria leads to impaired mitochondrial fatty acid β-oxidation and respiration, resulting in decreased ATP production. Diminished transport activity leads to the observed Fanconi syndrome. Keywords: Fanconi syndrome, mitochondriopathy, fatty acid oxidation, supercomplexes |
| Databáze: | OpenAIRE |
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