OXPHOS funtion in cardiopathy; New genes involved in Complex IV deficiency

SCIENTIFIC AREA
Cardiovascular Biology and Cardiovascular Diseases
CENTER
Departamento de Bioquímica (UAM)
VACANCIES
1
CONTACT E-MAIL
juan.arredondo@uam.es
DESCRIPTION OF THE OFFER

Cardiogenesis requires specified cells to differentiate into contracting, energetically competent cardiomyocytes. Cardiac specification implies several critical steps among which the coordination of genetic circuits with developmental energetics are crucial. The beating Drosophila heart tube provides an excellent, simple and efficient in vivo system to study the molecular mechanisms that control the developmental and physiological processes of heart differentiation and function.

 

In humans, one of the most frequent OXPHOS defects associated to cardiomyopathy is cytochrome c oxidase (COX or Complex IV) deficiency caused by mutations in COX assembly factors like Sco1 and Sco2. To investigate the molecular mechanisms that underlie the cardiomyopathy associated with SCO function deficiency, we have heart specifically interfered scox, the single Drosophila sco orthologue. In this context, to study the role played by mitochondria in Drosophila cardiac function in vivo we are carrying out a heart functional and physiological analysis in which young or aged cardio-specifically interfered flies are compared to wild type flies

 

Cardiac-specific knockdown of scox (scox KD) reduces fly lifespan and severely compromises heart function and structure, producing dilated cardiomyopathy. Cardiomyocytes with low scox RNA levels have a significant reduction in COX activity and undergo a metabolic switch from OXPHOS to glycolysis, mimicking the clinical features found in patients harbouring Sco mutations. A significant increase in p53 dependent apoptosis is the major cause of the cardiac defects observed. Remarkably, Sco2 knock-out mice have enhanced apoptosis in muscle and liver, clearly suggesting that cell death is a key feature of the COX deficiencies produced by mutations in Sco genes in humans (Martinez-Morentin et al 2015). In this line, we are currently following two independent paths.

 

First, we are investigating the role played by energy homeostasis signalling pathways in cardiomyopathy development. Since TOR interference rescues the cardiomyopathy phenotype, we are assessing its role in the metabolic response induced by scox KD, dp53 expression and apoptosis. Moreover, within the same line, we are studying tissue and organ interrelationship. Thus, we have focused our interests in whether the same pathways are involved in disease development in other tissues as well as the role played by other organs and tissues in cardiomyopathy development.

 

Second, we are investigating the role played by other mitochondrial proteins in scox KD related cardiomyopathy and its putative implication in retrograde signalling. In particular, since scox has a well-conserved thioreductase activity, we are investigating the role played by intermembrane space re-dox regulated pathways in mitochondrial pathologies with a special focus on their interaction with scox.

MASTER
Biomolecules & Cell D.
Molecular Biomedicine
Biotechnology