A new enzyme and pathway in cardiolipin synthesis
Robin Duncan, Assistant Professor, University of Waterloo, Waterloo, Ontario, Canada

Award—US $50,000 over 2-year period

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

Abstract:

Barth syndrome is caused by mutations in the tafazzin gene. Tafazzin is a transacylase that functions in the remodelling of cardiolipin (CL) by catalyzing the transfer of linoleic acid (18:2n6) from phosphatidylcholine (PC) to monolysocardiolipin (MLCL), which helps to produce CL that is enriched in 18:2n6. People with Barth syndrome produce less tetralinoleoyl CL, and they also have less total CL and more MLCL in their cells. Since properly formed CL is critical for mitochondrial energy metabolism, this causes problems with the heart, skeletal muscle, neurons, and other tissues that have high metabolic rates. There is currently no specific treatment for Barth syndrome, and no specific treatments available to increase CL synthesis. We have discovered evidence of a new enzyme in CL synthesis. We detect this enzyme mainly in the mitochondria of cells, and we have found that expressing this enzyme in cultured cells increases the total amount of CL by 50%, without significantly changing levels of other phospholipids. We have also found that CL in those cells has a higher content of saturated fats, and may have a higher level of 18:2n6 as well. When we grind up those cells, we find that they are better at making CL from either MLCL or dilysocardolipin (DLCL), so we think that this enzyme is a brand new CL synthesis enzyme. We want to study it in detail, to find out how it works, and to see if it can help cultured cells from Barth syndrome patients make more CL and make better CL, and if it can help their mitochondria function better. We hope that results from this work will be a first step in identifying a potential treatment for Barth syndrome.