Assmann, N; Dettmer, K; Simbuerger, JMB; Broeker, C; Nuernberger, N; Renner, K; Courtneidge, H; ... Reinders, J; + view all Assmann, N; Dettmer, K; Simbuerger, JMB; Broeker, C; Nuernberger, N; Renner, K; Courtneidge, H; Klootwijk, ED; Duerkop, A; Hall, A; Kleta, R; Oefner, PJ; Reichold, M; Reinders, J; - view fewer (2016) Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy. Cell Reports , 15 (7) pp. 1423-1429. 10.1016/j.celrep.2016.04.037.

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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.

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