Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy

Abstract

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