Chicco 2012 Abstract Bioblast
|Chicco AJ (2012) Substrate-specific impairment of cardiac mitochondrial respiration in Taz-deficient mice: Insight into the pathogenesis of Barth Syndrome. Mitochondr Physiol Network 17.12.|
Chicco AJ (2012)
Event: Bioblast 2012
Barth syndrome (BTHS) is an X-linked cardioskeletal myopathy resulting from a mutation in the Tafazzin (Taz) gene encoding a mitochondrial transacylase required for the remodeling of cardiolipin (CL). CL is an inner membrane phospholipid essential for the function of several mitochondrial proteins, but it remains unclear how Taz deficiency or aberrant CL remodeling lead to mitochondrial dysfunction and cardiomyopathy. In this study, the cardiac mitochondrial phenotype of a new Taz shRNA mouse model of BTHS was characterized. High-resolution respirometry revealed 40-50% lower OXPHOS rates in Taz vs. wild-type (WT) mitochondria using pyruvate and palmitoylcarnitine (PC) as substrates (P < 0.001). Succinate respiration was also lower in Taz, but only by 13% (P = 0.07), suggesting a possible defect in Complex I and/or NADH generation from pyruvate and PC oxidation. Interestingly, glutamate respiration was 46% greater in Taz vs. WT (P < 0.05), and reached OXPHOS rates equal to that obtained with pyruvate and PC in WT mitochondria. Analysis of the Taz mitochondrial proteome revealed deficiencies in enzymes involved in beta-oxidation, pyruvate transport, amino acid catabolism, complex I, and the TCA cycle. However, malate dehydrogenase, the primary source of NADH from glutamate oxidation, was elevated 40% in Taz vs. WT mice (P < 0.05). Cardiac metabolomic profiling revealed an accumulation of substrates congruent with observed mitochondrial enzyme deficiencies. Mitochondrial ROS release and sensitivity to Ca2+-induced permeability transition (MPT) were both reduced in Taz vs. WT mitochondria. Taken together, these data suggest that Taz deficiency selectively impairs carbohydrate and lipid oxidation, and argues against a significant role of respiratory chain dysfunction, ROS production, or MPT in the pathogenesis of Barth syndrome.
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• Keywords: Barth syndrome, Cardiolipin
• O2k-Network Lab: US CO Fort Collins Chicco AJ
Labels: MiParea: Respiration, Genetic knockout;overexpression Pathology: Other Stress:Oxidative stress;RONS Organism: Mouse Tissue;cell: Heart
Enzyme: Complex I, Complex II;succinate dehydrogenase Regulation: mt-Membrane potential, Fatty acid
Pathway: N, S HRR: Oxygraph-2k
Department of Health and Exercise Science, Colorado State University; Email: firstname.lastname@example.org
Funding: American Heart Association and the Barth Syndrome Foundation