Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy

Cell Rep. 2016 May 17;15(7):1423-1429. doi: 10.1016/j.celrep.2016.04.037. Epub 2016 May 5.


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.

Keywords: Fanconi syndrome; fatty acid oxidation; mitochondriopathy; supercomplexes.

MeSH terms

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


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