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.

Link: MiPNet17.12 Bioblast 2012 - Open Access

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.

• Keywords: Barth syndrome, Cardiolipin

• O2k-Network Lab: US CO Fort Collins Chicco AJ

Labels:

Stress:RONS; Oxidative Stress"RONS; Oxidative Stress" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property., Mitochondrial Disease; Degenerative Disease and Defect"Mitochondrial Disease; Degenerative Disease and Defect" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property., Genetic Defect; Knockdown; Overexpression"Genetic Defect; Knockdown; Overexpression" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property. Organism: Mouse Tissue;cell: Cardiac muscle"Cardiac muscle" is not in the list (Heart, Skeletal muscle, Nervous system, Liver, Kidney, Lung;gill, Islet cell;pancreas;thymus, Endothelial;epithelial;mesothelial cell, Blood cells, Fat, ...) of allowed values for the "Tissue and cell" property.

Enzyme: Complex I, Complex II; Succinate Dehydrogenase"Complex II; Succinate Dehydrogenase" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property. Regulation: Membrane Potential"Membrane Potential" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property., Fatty Acid"Fatty Acid" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property.

HRR: Oxygraph-2k

Affiliations and author contributions

Department of Health and Exercise Science, Colorado State University; Email: [email protected]

Funding: American Heart Association and the Barth Syndrome Foundation

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