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Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy

Assmann, N; Dettmer, K; Simbuerger, JMB; Broeker, C; Nuernberger, N; Renner, K; Courtneidge, H; ... Reinders, J; + view all (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. Green open access

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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.

Type: Article
Title: Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2016.04.037
Publisher version: http://dx.doi.org/10.1016/j.celrep.2016.04.037
Language: English
Additional information: Copyright © 2016 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell Biology, Fatty-acid Oxidation, Beta-oxidation, 3-hydroxyacyl-coa Dehydrogenase, Trifunctional Protein, Phosphorylation, Tubule, Cells, Coa, Atp, Specificity
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1493687
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