Assmann 2014 PhD Thesis: Difference between revisions
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{{Publication | {{Publication | ||
|title= | |title=Assmann N (2015) Impact of Fanconi-associated protein on the mitochonrial proteome. PhD Thesis 1-111. | ||
|info=[http://epub.uni-regensburg.de/32453/ PDF] | |info=[http://epub.uni-regensburg.de/32453/ PDF] | ||
|authors= | |authors=Assmann N | ||
|year=2015 | |year=2015 | ||
|journal=PhD Thesis | |journal=PhD Thesis | ||
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{{Labeling | {{Labeling | ||
|area=Respiration, Comparative MiP;environmental MiP | |area=Respiration, Comparative MiP;environmental MiP | ||
|diseases=Other | |||
|organism=Pig | |organism=Pig | ||
|tissues=Kidney | |tissues=Kidney, Other cell lines | ||
|preparations=Intact cells, Permeabilized cells | |preparations=Intact cells, Permeabilized cells | ||
|couplingstates=LEAK, ROUTINE, OXPHOS, ET | |||
|pathways=F, N, S, CIV, NS, ROX | |||
|couplingstates=LEAK, ROUTINE, OXPHOS, | |||
| | |||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
}} | }} |
Latest revision as of 15:32, 4 October 2018
Assmann N (2015) Impact of Fanconi-associated protein on the mitochonrial proteome. PhD Thesis 1-111. |
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Assmann N (2015) PhD Thesis
Abstract: This work describes the analysis of a novel, isolated, autosomal dominant form of FanconiΒ΄s syndrome, a disorder of the renal proximal tubule associated with decreased reapsorption of solutes from the primary urine. This yet unknown FanconiΒ΄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 βFanconi-associated proteinβ, 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 Ξ²-oxidation. The incorporation into MTP impairs both mitochondrial Ξ²-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 Ξ²-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 Ξ²-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 FanconiΒ΄s syndrome.
β’ O2k-Network Lab: DE Regensburg Renner-Sattler K
Labels: MiParea: Respiration, Comparative MiP;environmental MiP
Pathology: Other
Organism: Pig Tissue;cell: Kidney, Other cell lines Preparation: Intact cells, Permeabilized cells
Coupling state: LEAK, ROUTINE, OXPHOS, ET
Pathway: F, N, S, CIV, NS, ROX
HRR: Oxygraph-2k