Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy.
Cell Rep
; 15(7): 1423-1429, 2016 05 17.
Article
em En
| MEDLINE
| ID: mdl-27160910
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 ß-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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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doenças Mitocondriais
/
Síndrome de Fanconi
/
Rim
/
Mitocôndrias
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article