Abstract 18250: Tafazzin-Knockdown Mice: Heart Mitochondrial Structure and Function
Barth syndrome is a genetic disorder with mutations in the tafazzin gene resulting in cardiomyopathy, hypotonia, growth delays, and cyclic neutropenia. Mitochondria have been examined for functional defects in Barth syndrome and defects found in oxidative phosphorylation, a decreased content and abnormal composition of cardiolipin, and an increased content of monolysocardiolipin. Consequently, mitochondrial dysfunction resulting from the cardiolipin abnormality has been posited as the primary cause for pathology in Barth syndrome. However, the mechanisms that link cardiolipin abnormality, mitochondrial dysfunction, and the various pathological conditions in Barth syndrome are still unknown. We studied isolated heart subsarcolemmal and interfibrillar mitochondria from tafazzin knockdown mice to examine the role of cardiolipin in mitochondrial dysfunction. In the knockdown mice, the cristae assume the shape of Florence flasks, so we designate them as “florentine”. They have a narrow tubular neck connected directly to the boundary membrane_these are the crista junctions, which in these organelles are of exaggerated length. In mitochondria from tafazzin knockdown mice, the yield of mitochondrial protein is similar to wild type, but the content of cardiolipin decreased by 50 %, monolysocardiolipin increased 25-fold, and unsaturated acyl chains increased. In both mitochondrial populations, state-3 respiration using glutamate plus malate, succinate (+rotenone), and acetylcarnitine plus malate was similar to wild type mice. However, state-3 respiration was decreased with palmitoylcarnitine plus malate (both @-25%;p<0.05) and pyruvate plus malate (subsarcolemmal -25%, p<0.05; interfibrillar -14%, p NS), localizing defects to these separate processes, not the oxidative side of oxidative phosphorylation. Mitochondria from knockdown mice did not generate increased reactive oxygen species. Despite a 50 % decrease in cardiolipin content there is only a mild selective defect in mitochondrial function in this mouse model. However, this change in cardiolipin might be involved in the morphological and perhaps physiological alteration of crista junctions.
- Energy metabolism
- Cardiac metabolism
- Mitochondrial energetics, heart failure, arrhythmias
- Transgenic models
- © 2013 by American Heart Association, Inc.