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The cause and consequences of plasmalogen depletion in Barth syndrome

The cause and consequences of plasmalogen depletion in Barth syndrome
Richard Epand, PhD, Professor, McMaster University, Hamilton, Ontario, Canada

Award: US $50,000 over 1-year period

*Partial funding for this award was provided by Barth Syndrome Foundation of Canada


We have shown that the greatest change in the lipid content of the heart of mice that have been knocked down for tafazzin is the decrease in plasmalogen. We have shown that this is not a consequence of a decrease in the rate of synthesis of plasmalogen precursors in peroxisomes. For the purpose of the proposed studies we will use lymphoblasts derived from Barth syndrome patients that is ideal for studies of the mechanism. It is a single cell type that can be grown in culture and used for subcellular fractionation studies to measure lipid components in different organelles. We have already begun some of this work and together with Dr. Schlame, we have shown that there is a decrease in plasmalogen (in this case plasmenylethanolamine as the dominant form) in these cells. We will compare the whole cell with isolated mitochondria and with endoplasmic reticulum. The endoplasmic reticulum is where the synthesis of plasmalogens is completed and the mitochondria where tafazzin is located, whose presence changes the plasmalogen levels. This will further specify the mechanism for the loss of plasmalogens. We will also study the consequence of the elimination of the activity of certain enzymes involved in lipid metabolism on the levels of both plasmalogens and cardiolipin. This will first be done with specific enzyme inhibitors and subsequently confirmed with gene knock out studies. In addition, O-hexadecylglycerol is a precursor of plasmalogens and has been shown to increase the rate of plasmalogen synthesis in cells. We expect that the addition of O-hexadecylglycerol will compensate for the loss of plasmalogens and restore plasmalogen levels to normal in the lymphoblasts derived from Barth syndrome patients. What we are anxious to determine is whether this nutrient will also restore the level of cardiolipin since there is an apparent inter-relationship in the metabolism of these two lipids.

The focus of lipid studies in relation to Barth syndrome has been on changes in cardiolipid metabolism. However, we have recently shown that the greatest change in lipid levels in tissues with reduced levels of tafazzin is a loss of plasmalogens. This loss of one of the major lipid components in heart mitochondria will almost certainly have consequences on the properties of these mitochondria. In the proposed studies we will focus on the questions of how the loss of tafazzin function results in changes in plasmalogen metabolism. We will also study how restoration of plasmalogen levels affect other mitochondrial activities, in particular the restoration of cardiolipin. The results will suggest new targets for the treatment and diagnosis of Barth syndrome.

Associated Publications to Date:

Kimura T, Kimura AK, Ren M, Monteiro V, Xu Y, Berno B, Schlame M, Epand RM. Plasmalogen loss caused by remodeling deficiency in mitochondria.  Life Sci Alliance. 2019 Aug 21;2(4). pii: e201900348. doi:10.26508/lsa.201900348. Print 2019 Aug. (PubMed - Open Access)*

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