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

Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy.

Author information

1
Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
2
Medical Cell Biology, University of Regensburg, 93053 Regensburg, Germany.
3
Department of Hematology and Oncology, University Clinic Regensburg, 93053 Regensburg, Germany.
4
Centre for Nephrology, University College London, London NW3 2PF, UK.
5
Institute of Analytical Chemistry, University of Regensburg, 93053 Regensburg, Germany.
6
Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland.
7
Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany. Electronic address: joerg.reinders@ukr.de.

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.

KEYWORDS:

Fanconi syndrome; fatty acid oxidation; mitochondriopathy; supercomplexes

PMID:
27160910
DOI:
10.1016/j.celrep.2016.04.037
[Indexed for MEDLINE]
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