Dhandapani 2014 Abstract IOC 2014-04 Schroecken
|Dhandapani PK, Dufour E, Jacobs HT, Szibor M (2014) Alternative oxidase-based therapy for heart failure. Mitochondr Physiol Network 19.02.|
Event: MiPNet19.02 IOC88
Cardiomyopathies are a leading cause of heart failure (HF) and death in the western world. The ultimate treatment, heart transplantation, is a huge financial burden for the society, but also a sociological burden for the patients and their families since it only shifts the suffering to the next level. There are numerous etiologies for HF of which, the involvement of mitochondrial dysfunctions came more into focus. Especially, in the failing heart, the activity of Complex IV of the respiratory system is depressed. Plants and many lower organisms, except mammals, express alternative oxidases (AOX) that branch the mitochondrial electron transportation and maintain electron flow under conditions where the cytochrome pathway of the respiratory system is blocked. We propose an AOX-based therapy in HF that could consequently represent a causative therapy approach for mitochondrial based HF, for which, we generated a mouse model expressing transgenic AOX.
AOXRosa26 mice were generated by a site-directed integration of Ciona intestinalis AOX into the ROSA26 locus via homologous recombination, where a strong and ubiquitous CAG promoter controls its expression. AOX protein was expressed in all tissues studied except for brain. Despite its high expression level, AOX had no obvious adverse effect on the general mouse phenotype or expression levels of other mitochondrial respiratory chain subunits. AOX RNA expression was analyzed by Northern blotting which correlated with the protein expression levels. Where expressed, AOX confers respiratory resistance to azide and antimycin A. We will study the hypothesis that cardiomyopathies of different etiologies are based on mitochondrial dysfunction. If mitochondrial respiratory chain complexes III or IV are the cause for the disease, AOX expression should rescue or alleviate the symptoms. We will challenge cardiac functions in different mouse models of cardiomyopathy by spatio-temporal manipulation of specific gene expression.
AOXRosa26 mice are designed to serve as a resourceful and novel tool to study mitochondrial dysfunctions in vivo. In combination with disease models for heart failure, AOXRosa26 will aid in understanding better, the underlying molecular mechanisms, and will reveal perspectives on organization and function of the mitochondrial respiratory chain.
Labels: MiParea: Respiration, Genetic knockout;overexpression
Organism: Mouse Tissue;cell: Heart
Enzyme: Complex IV;cytochrome c oxidase
Pathway: Other combinations HRR: Oxygraph-2k
Praveen K. Dhandapani (1), E. Dufour (3), H.T. Jacobs (1,3), M. Szibor (1,2)
- Research Program of Molecular Neurology, University of Helsinki, Biomedicum Helsinki 1, Helsinki, Finland
- Dept. I – Cardiac Development and Remodeling, Max Planck Institute of Heart and Lung Research, Bad Nauheim, Germany
- Institute of Biomedical Technology, University of Tampere, Tampere, Finland