Cardiac metabolic pathways affected in the mouse model of barth syndrome

Yan Huang, Corey Powers, Satish K. Madala, Kenneth D. Greis, Wendy D. Haffey, Jeffrey Towbin, Enkhsaikhan Purevjav, Sabzali Javadov, Arnold W. Strauss, Zaza Khuchua

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Tazdeficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS.

Original languageEnglish (US)
Article numbere0128561
JournalPLoS One
Volume10
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

Barth Syndrome
electron transport chain
Electron Transport
Metabolic Networks and Pathways
biochemical pathways
Mitochondria
animal models
Cardiolipins
cardiolipins
mitochondria
NADH dehydrogenase (ubiquinone)
beta oxidation
Proteomics
heart
myocardium
Myocardium
Long-Chain Acyl-CoA Dehydrogenase
Enzymes
Fatty Acids
3-Hydroxyacyl-CoA Dehydrogenase

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Huang, Y., Powers, C., Madala, S. K., Greis, K. D., Haffey, W. D., Towbin, J., ... Khuchua, Z. (2015). Cardiac metabolic pathways affected in the mouse model of barth syndrome. PLoS One, 10(6), [e0128561]. https://doi.org/10.1371/journal.pone.0128561

Cardiac metabolic pathways affected in the mouse model of barth syndrome. / Huang, Yan; Powers, Corey; Madala, Satish K.; Greis, Kenneth D.; Haffey, Wendy D.; Towbin, Jeffrey; Purevjav, Enkhsaikhan; Javadov, Sabzali; Strauss, Arnold W.; Khuchua, Zaza.

In: PLoS One, Vol. 10, No. 6, e0128561, 01.06.2015.

Research output: Contribution to journalArticle

Huang, Y, Powers, C, Madala, SK, Greis, KD, Haffey, WD, Towbin, J, Purevjav, E, Javadov, S, Strauss, AW & Khuchua, Z 2015, 'Cardiac metabolic pathways affected in the mouse model of barth syndrome', PLoS One, vol. 10, no. 6, e0128561. https://doi.org/10.1371/journal.pone.0128561
Huang, Yan ; Powers, Corey ; Madala, Satish K. ; Greis, Kenneth D. ; Haffey, Wendy D. ; Towbin, Jeffrey ; Purevjav, Enkhsaikhan ; Javadov, Sabzali ; Strauss, Arnold W. ; Khuchua, Zaza. / Cardiac metabolic pathways affected in the mouse model of barth syndrome. In: PLoS One. 2015 ; Vol. 10, No. 6.
@article{e1ef586c9cae4ec0a226197fcfe846f6,
title = "Cardiac metabolic pathways affected in the mouse model of barth syndrome",
abstract = "Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Tazdeficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS.",
author = "Yan Huang and Corey Powers and Madala, {Satish K.} and Greis, {Kenneth D.} and Haffey, {Wendy D.} and Jeffrey Towbin and Enkhsaikhan Purevjav and Sabzali Javadov and Strauss, {Arnold W.} and Zaza Khuchua",
year = "2015",
month = "6",
day = "1",
doi = "10.1371/journal.pone.0128561",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

TY - JOUR

T1 - Cardiac metabolic pathways affected in the mouse model of barth syndrome

AU - Huang, Yan

AU - Powers, Corey

AU - Madala, Satish K.

AU - Greis, Kenneth D.

AU - Haffey, Wendy D.

AU - Towbin, Jeffrey

AU - Purevjav, Enkhsaikhan

AU - Javadov, Sabzali

AU - Strauss, Arnold W.

AU - Khuchua, Zaza

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Tazdeficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS.

AB - Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Tazdeficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS.

UR - http://www.scopus.com/inward/record.url?scp=84932611000&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84932611000&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0128561

DO - 10.1371/journal.pone.0128561

M3 - Article

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 6

M1 - e0128561

ER -