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Lindenberg 2013 Abstract MiP2013

From Bioblast
Lindenberg K, Matallo J, Fleischer C, Lenk T, Lehnert S, Jahn O, Otto M, Calzia E, Landwehrmeyer GB (2013) Similar alterations in mitochondrial proteome of brain and skeletal muscle in two transgenic mouse models for Huntington´s disease. Mitochondr Physiol Network 18.08.

Link:

Katrin Lindenberg

MiP2013, Book of Abstracts Open Access

Lindenberg K, Matallo J, Fleischer C, Lenk T, Lehnert S, Jahn O, Otto M, Calzia E, Landwehrmeyer GB (2013)

Event: MiPNet18.08_MiP2013

Several observations indicate that mitochondrial dysfunction plays an important role in Huntington´s disease (HD) pathogenesis. HD patients lose significantly body weight despite normal or increased food intake and impairment of ATP synthesis occurs even in pre-motor manifest HD expansion mutation carriers. Until now the molecular mechanisms linking mutant huntingtin to mitochondrial dysfunction are not known. To get a more detailed picture of mitochondrial changes in HD, mitochondria of brain and skeletal muscle from two different mouse models for HD (R6/2 mice and HdhQ-knock in mouse) were isolated and the mitochondrial proteomes of the HD mice and respective controls were compared using a 2D-DIGE (2-dimensional differential in-gel electrophoresis) approach.

After optimizing the isolation of mitochondria using differential centrifugation, the purity of the mitochondrial fraction was confirmed by Western Blot. Mitochondrial lysates were then used for proteome analysis. In mitochondria of R6/2 mouse brains mitochondrial proteins of the citric acid cycle, the amino acid degradation pathway, mitochondrial fusion and heat shock proteins were increased. Surprisingly, only a minority of selected mitochondrial proteins were downregulated in the R6/2 mice. Alterations of mitochondrial proteome in skeletal muscle included an upregulation of several proteins of the citric acid cycle, the electron transfer-pathway, ATP synthesis, fatty acid metabolism, amino acid degradation and heat shock proteins. The mitochondrial proteome alterations in the knock-in mouse model were similar, although the total number of differently expressed mitochondrial proteins was lower. In contrast, when comparing the amount of certain differential expressed mitochondrial proteins by Western Blot using whole tissue lysates of brain or skeletal muscle, respectively, downregulation of these proteins was observed.

In summary, these results show similar changes in the proteome of purified mitochondria in brain and skeletal muscle of two different mouse models for HD. Unexpectedly, the majority of differentially expressed mitochondrial proteins in the R6/2 and HdhQ mice were upregulated. Whereas these upregulations for some mitochondrial proteins in whole tissue lysates could not be confirmed by Western blot, suggesting that a possible overall lower number of mitochondria is compensated by an upregulation of several metabolic pathways, reflecting at least in part compensatory changes. Currently high-resolution respirometry measurements are performed on samples from brain and skeletal muscle of the 2 HD mouse models to study possible alterations of respiratory system function and respiratory capacities due to the observed changes in the mitochondrial proteome.


O2k-Network Lab: DE Ulm Radermacher P


Labels: MiParea: Respiration, mt-Biogenesis;mt-density, nDNA;cell genetics, Genetic knockout;overexpression, mt-Medicine  Pathology: Neurodegenerative 

Organism: Mouse  Tissue;cell: Skeletal muscle, Nervous system  Preparation: Isolated mitochondria 


Coupling state: OXPHOS 

HRR: Oxygraph-2k 

MiP2013, Huntington's 

Affiliations and author contributions

1 - Experimental Neurology, Ulm University, Germany;

2 - Dept of Anesthesia, Section of Anesthesiology, Pathophysiology and process development, Ulm University, Germany;

3 - Max-Planck-Institute for Experimental Medicine, Göttingen, Germany.

Email: [email protected]