Assmann 2016 Cell Rep
|Assmann N, Dettmer K, Simbuerger JM, Broeker C, Nuernberger N, Renner K, Courtneidge H, Klootwijk ED, Duerkop A, Hall A, Kleta R, Oefner PJ, Reichold M, Reinders J (2016) Renal fanconi syndrome is caused by a mistargeting-based mitochondriopathy. Cell Rep 15:1423-9.|
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.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
• Keywords: Fanconi syndrome, Fatty acid oxidation, Mitochondriopathy, Supercomplexes, Pig kidney LLC-PK1 cells
• O2k-Network Lab: DE Regensburg Renner-Sattler K
Labels: MiParea: Respiration, Genetic knockout;overexpression Pathology: Other
Organism: Pig Tissue;cell: Kidney, Other cell lines Preparation: Intact cells Enzyme: Supercomplex
Coupling state: LEAK, OXPHOS, ET Pathway: F, N, S, NS, Other combinations, ROX HRR: Oxygraph-2k