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: Nadine Assmann, Katja Dettmer, Johann M B Simbuerger, Carsten Broeker, Nadine Nuernberger, Kathrin Renner, Holly Courtneidge, Enriko D Klootwijk, Axel Duerkop, Andrew Hall, Robert Kleta, Peter J Oefner, Markus Reichold, Joerg Reinders
• Journal: Cell reports (Cell Rep) Vol. 15 Issue 7 Pg. 1423-1429 (05 17 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 27160910 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Cell Extracts
• Fatty Acids
• Peroxisomal Bifunctional Enzyme
• Sodium-Potassium-Exchanging ATPase

Topics

• Animals
• Biological Transport
• Cell Extracts
• Energy Metabolism
• Fanconi Syndrome (complications, metabolism, pathology)
• Fatty Acids (metabolism)
• Kidney (metabolism, pathology)
• LLC-PK1 Cells
• Microscopy, Confocal
• Mitochondria (metabolism)
• Mitochondrial Diseases (complications, metabolism, pathology)
• Mutation (genetics)
• Oxidation-Reduction
• Peroxisomal Bifunctional Enzyme (metabolism)
• Proteomics
• Sodium-Potassium-Exchanging ATPase (metabolism)
• Subcellular Fractions (metabolism)
• Swine