Difference between revisions of "Chicco 2012 Abstract Bioblast"
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{{Abstract | {{Abstract | ||
|title=Chicco AJ (2012) Substrate-specific impairment of cardiac mitochondrial respiration in Taz-deficient mice: | |title=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. | ||
|info=[[MiPNet17.12 Bioblast 2012|MiPNet17.12 Bioblast 2012 - Open Access]] | |info=[[MiPNet17.12 Bioblast 2012|MiPNet17.12 Bioblast 2012 - Open Access]] | ||
|authors=Chicco AJ | |authors=Chicco AJ | ||
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|abstract=[[File:Chicco Headshot.jpg|right|150px|Adam Chicco]] | |abstract=[[File:Chicco Headshot.jpg|right|150px|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 Ca<sup>2+</sup>-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. | 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 Ca<sup>2+</sup>-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. | ||
# [http://www.ncbi.nlm.nih.gov/pubmed/16899548 Chicco AJ, Sparagna GC (2007) Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am J Physiol Cell Physiol 292: C33-C44. Open Access] | |||
# [http://www.ncbi.nlm.nih.gov/pubmed?term=Cardiac%20and%20skeletal%20muscle%20defects%20in%20a%20mouse%20model%20of%20human%20Barth%20syndrome Acehan D, Vaz F, Houtkooper RH, James J, Moore V, Tokunaga C, Kulik W, Wansapura J, Toth MJ, Strauss A, Khuchua Z (2011) Cardiac and skeletal muscle defects in a mouse model of human Barth syndrome. J Biol Chem 286: 899-908. Open Access] | |||
# [http://www.ncbi.nlm.nih.gov/pubmed/16973164 Schlame M, M Ren (2006) Barth syndrome, a human disorder of cardiolipin metabolism. FEBS Lett 580: 5450-5455.] | |||
|keywords=Barth syndrome, Cardiolipin | |keywords=Barth syndrome, Cardiolipin | ||
|mipnetlab=US CO Fort Collins Chicco AJ | |mipnetlab=US CO Fort Collins Chicco AJ | ||
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}} | }} | ||
{{Labeling | {{Labeling | ||
|area=Respiration, Genetic knockout;overexpression | |||
|organism=Mouse | |||
|tissues=Heart | |||
|enzymes=Complex I, Complex II;succinate dehydrogenase | |||
|injuries=Oxidative stress;RONS | |||
|diseases=Other | |||
|topics=mt-Membrane potential, Fatty acid | |||
|pathways=N, S | |||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|journal=Mitochondr Physiol Network | |journal=Mitochondr Physiol Network | ||
|articletype=Abstract | |articletype=Abstract | ||
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== Help == | == Help == | ||
* [[MitoPedia: Terms and abbreviations]] | |||
* [[MitoPedia | |||
Latest revision as of 15:57, 7 November 2016
| 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.
- Chicco AJ, Sparagna GC (2007) Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am J Physiol Cell Physiol 292: C33-C44. Open Access
- Acehan D, Vaz F, Houtkooper RH, James J, Moore V, Tokunaga C, Kulik W, Wansapura J, Toth MJ, Strauss A, Khuchua Z (2011) Cardiac and skeletal muscle defects in a mouse model of human Barth syndrome. J Biol Chem 286: 899-908. Open Access
- Schlame M, M Ren (2006) Barth syndrome, a human disorder of cardiolipin metabolism. FEBS Lett 580: 5450-5455.
• 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
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
