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Assmann 2014 PhD Thesis
Coupling states LEAK  + , ROUTINE  + , OXPHOS  + , ET  +
Diseases Other  +
Has abstract This work describes the analysis of a nove
This work describes the analysis of a novel, isolated, autosomal dominant form of Fanconi´s syndrome, a disorder of the renal proximal tubule associated with decreased reapsorption of solutes from the primary urine. This yet unknown Fanconi´s syndrome is evoked by a mutation in the third codon of the peroxisomal protein enoyl-CoA hydratase / L-3-hydroxyacyl-CoA dehydrogenase (EHHADH), also called “Fanconi-associated protein”, which results in the substitution of a glutamic acid residue with lysine (p.E3K). By complementing proteomic and metabolomic analyses of wildtype- and mutant-EHHADH-expressing proximal tubular cell lines (LLC-PK1) with different biochemical and cell biological investigations, the underlying pathomechanism is elucidated. The E3K-mutation leads to the erroneous localization of peroxisomal EHHADH into mitochondria causing a mitochondriopathy. Upon mistargeting of EHHADHMUT into mitochondria, it replaces an alpha subunit of the mitochondrial trifunctional protein (MTP). The MTP normally builds a heterooctamer consisting of four alpha and four beta subunits and is involved in mitochondrial fatty acid β-oxidation. The incorporation into MTP impairs both mitochondrial β-oxidation and respiratory supercomplex assembly, leading to a decreased oxidative phosphorylation capacity. Impairment of the former is shown by the characteristic accumulation of hydroxyacyl-, enoyl- and acylcarnitines in the cell culture supernatant, thus resembling the situation in patients with MTP and/or LCHAD deficiency. The impaired mitochondrial β-oxidation consequently decreases cellular long-chain fatty acid uptake and the acetyl-CoA production in EHHADHMUT cell line. In addition, EHHADHMUT is also incorporated into respiratory supercomplexes, thereby disturbing their assembly, as shown by blue native PAGE. As a result of impaired mitochondrial β-oxidation and diminished supercomplex assembly the EHHADHMUT cell line shows a decreased oxidative phosphorylation capacity and reduced ATP generation. This mitochondriopathy results in the decreased tubular reabsorption of electrolytes and low-molecular-weight proteins, leading to the Fanconi´s syndrome.
oteins, leading to the Fanconi´s syndrome.  +
Has info [ PDF]  +
Has title Assmann N (2015) Impact of Fanconi-associated protein on the mitochonrial proteome. PhD Thesis 1-111.  +
Instrument and method Oxygraph-2k  +
Mammal and model Pig  +
MiP area Respiration  + , Comparative MiP;environmental MiP  +
Pathways F  + , N  + , S  + , CIV  + , NS  + , ROX  +
Preparation Permeabilized cells  + , Intact cells  +
Tissue and cell Kidney  + , Other cell lines  +
Was published by MiPNetLab DE Regensburg Renner-Sattler K +
Was published in journal PhD Thesis +
Was published in year 2015  +
Was written by Assmann N +
Categories Publications
Modification date
"Modification date" is a predefined property that corresponds to the date of the last modification of a subject and is provided by Semantic MediaWiki.
13:32:26, 4 October 2018  +
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