Reduced mitochondrial activity is associated to altered mitochondrial dynamics in Down?s Syndrome cells

PABLO R. HELGUERA

washington

Workshop; 2013 Cognition in Down Syndrome Workshop; 2013

NIH-UCDENVER

Down?s syndrome (DS) is the most common human aneuploidy, and the most frequent genetic cause of mental retardation. We recently showed that DS cells exhibit high levels of oxidative stress, preventively downregulate mitochondrial function in order to minimize ROS production, and as a side effect, compromises energy sensitive processes (Helguera et al., 2013, Cell Metabolism 17,132-140). There is also a distinct mitochondrial morphotype associated with DS cells. Here we examined the relation between unusual mitochondrial morphologies and the dynamics of the mitochondrial network in DS primary neuronal cells and astrocytes. We developed a photoconvertible mitochondrial targeted fluorophore as a tool to measure fussion rates. DS cells present significantly reduced dynamic rates, a deficit partially reverted by boosting energy production. Dynamics rescue was also achieved by manipulating the expression of proteins related to mitochondrial fusion and fission (mitofusins 1 and 2, and Drp1). Microarray analysis excluded changes in mitofusin expression between NL and DS cells. As exchange of contents in mitochondrial network is crucial for its proper function, we are currently evaluating enhanced cell survival in DS cells with stable mitofusin overexpression, which may prove effective to prevent DS-related clinical phenotypes associated with mitochondrial dysfunction.