Chicco 2012 Abstract Bioblast

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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.

Link: MiPNet17.12 Bioblast 2012 - Open Access

Chicco AJ (2012)

Event: Bioblast 2012

Adam Chicco

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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  3. Schlame M, M Ren (2006) Barth syndrome, a human disorder of cardiolipin metabolism. FEBS Lett 580: 5450-5455.

Barth syndrome, Cardiolipin MiPNetLab: US CO Fort Collins Chicco AJ

Labels: MiParea: Respiration, Genetic knockout;overexpression Mammal;model: Mouse Tissue;cell: Heart  Enzyme: Complex I, Complex II;succinate dehydrogenase Stress: Oxidative stress;RONS Pathology: Other Regulation: mt-Membrane potential, Fatty acid Substrate state: CI, CII HRR: Oxygraph-2k 

Affiliations and author contributions

Department of Health and Exercise Science, Colorado State University; Email:

Funding: American Heart Association and the Barth Syndrome Foundation


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