Mitochondria are membrane-rich organelles that are essential to eukaryotic life. Detailed insight has emerged into the assembly and the dynamics of mitochondrial membrane proteins, but a fundamental gap has remained in understanding the dynamics of mitochondrial lipids. Barth syndrome (BTHS) is a disorder of the mitochondrial metabolism of lipids, in particular the mitochondria-specific lipid cardiolipin, and thus provides unique opportunity to address this gap in a context relevant to human health. The objective of this application is to identify the mechanism that causes partial replacement of cardiolipin by monolyso-cardiolipin in BTHS and to elucidate its functional consequences. This objective fits into our broad goals to understand the function of cardiolipin in mitochondria and to unravel the molecular pathophysiology of BTHS. BTHS is caused by mutations in tafazzin, a lipid acyltransferase, which leads to an inborn cardiomyopathy, in which the normal differentiation of myocardium is impaired. Based on our preliminary data, we hypothesize that cardiomyopathy in BTHS results from continuous degradation of cardiolipin, which lowers cardiolipin levels and perturbs the development of shapeless stem cell mitochondria to cristae-rich cardiomyocyte mitochondria. To investigate this hypothesis, we propose (i) to identify the mechanism by which tafazzin deficiency causes cardiolipin degradation, (ii) to determine the effect of cardiolipin depletion on cardiomyocyte differentiation, and (iii) to establish whether inhibition of cardiolipi degradation improves the function of cardiac mitochondria. Specifically, we will determine whether the increased turnover is caused by decreased cardiolipin unsaturation, increased cardiolipin oxidation, or altered cardiolipin localization within the membrane and we will identify the phospholipase that catalyzes cardiolipin degradation. In a mouse model with tafazzin knock-down, we will determine the embryologic stage at which cardiolipin is critical and define the consequences that the loss of cardiolipin has for cardiac differentiation. Finally, we will test tw drugs (resveratrol and bezafibrate) that are known to increase supercomplex assembly and of which we have shown that they inhibit cardiolipin degradation, to determine whether they improve cardiac function in the tafazzin knockdown mouse. The proposed study is significant because it will establish the molecular pathogenesis of BTHS and it will test a potential therapy of the disease in a mouse model. The results will close a critical gap in our knowledge of the role of mitochondria in the embryologic development of the heart by mapping out the transition from early mitochondria in progenitor cells to differentiated mitochondria in cardiomyocytes.

Public Health Relevance

The proposed project is relevant to public health because it will elucidate the pathogenesis of Barth syndrome, a developmental cardiomyopathy. The work will provide critical insight into the role of mitochondria in cardiac differentiation and demonstrte the effect of two drugs in a mouse model of the disease. Such results will support the NIH's mission to develop fundamental knowledge that will help to reduce the burden of human disability.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM115593-04
Application #
9545821
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Anderson, Vernon
Project Start
2015-09-01
Project End
2019-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Kimura, Tomohiro; Kimura, Atsuko K; Ren, Mindong et al. (2018) Substantial Decrease in Plasmalogen in the Heart Associated with Tafazzin Deficiency. Biochemistry 57:2162-2175
Schlame, Michael; Xu, Yang; Ren, Mindong (2017) The Basis for Acyl Specificity in the Tafazzin Reaction. J Biol Chem 292:5499-5506
Xu, Yang; Phoon, Colin K L; Berno, Bob et al. (2016) Loss of protein association causes cardiolipin degradation in Barth syndrome. Nat Chem Biol 12:641-7