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.
Highlights
Fanconi syndrome is a disorder of the proximal kidney tubule
The mutated protein interferes with mitochondrial energy production, which is predominantly based on fatty acid oxidation (FAO) in proximal tubular cells, leading to Fanconi syndrome
Subcellular Localization of Mutated EHHADH The p.E3K-mutation of EHHADHMUT leads to the generation of an N-terminal mitochondrial targeting sequence in addition to the native C-terminal peroxisomal targeting sequence (Klootwijk et al, 2014)
Summary
Fanconi syndrome is a disorder of the proximal kidney tubule. It is characterized by failure of the proximal tubule to reabsorb filtered molecules, causing urinary loss of amino acids, glucose, electrolytes, phosphate, and low-molecular-weight proteins. Klootwijk et al (2014) recently described a new form of inherited Fanconi syndrome caused by mutation of the EHHADH gene, which is highly expressed in human liver and kidney (Hoefler et al, 1994). EHHADH (enoyl-coenzyme A hydratase/L-3-hydroxyacyl-coenzyme A dehydrogenase) is a peroxisomal protein involved in b-oxidation of fatty acids. The mutated protein interferes with mitochondrial energy production, which is predominantly based on fatty acid oxidation (FAO) in proximal tubular cells, leading to Fanconi syndrome
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