Mechanism and role of cardiolipin oxidation and hydrolysis in Barth syndrome
Valerian Kagan, PhD, Professor and Vice-Chairman, University of Pittsburgh, Pittsburgh, PA  

Award—US $100,000 over 3-year period

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

Abstract:

In spite of the successful identification of the genetic defect in Barth syndrome (BTHS) - mutation of the gene encoding tafazzin (TAZ), an important regulator of cardiolipin (CL) re-acylation - its pathogenesis remains not fully understood resulting in the lack of mechanism-based therapeutic approaches. This necessitates further studies of biochemical mechanisms involved in the aberrant CL metabolism: a decrease in CL and an increase in mono-lyso-cardiolipin (MLCL) as well as an altered composition of CL molecular species. While the deficiency in MLCL re-acylation is clearly involved in the MLCL accumulation the upstream biochemical events driving CL metabolic modifications and causing its hydrolysis to yield MLCL have not been identified. Our central hypothesis is that production of reactive oxygen species (ROS) and CL oxidation followed by its hydrolysis represent essential upstream biochemical mechanisms triggering spiraling accumulation of different - oxygenated and non-oxygenated - CL hydrolysis products – MLCL, di-lyso-CL (DLCL), MLCLox, DLCLox, free fatty acids (FFA), FFAox, – which cause dysregulation of mitochondrial functions thus facilitating, in the absence of MLCL re-acylation, further accumulation of CL hydrolytic/oxidation metabolites. The following Specific Aims have been developed to experimentally test our hypothesis:

Specific Aim 1: To identify and quantify the products of CL oxidation and CLox hydrolysis in genetic cell models of BTHS.    

Specific Aim 2: To determine the effects of small molecule inhibitors of CL oxidation and CLox hydrolysis on BTHS-associated changes of molecular profiles of CL metabolites in cell models.

Specific Aim 3: To reveal molecular signatures and define the contribution of ROS, CL peroxidation and CLox hydrolysis to the characteristic molecular speciation of CL metabolites in a mouse BTHS model with k/down tafazzin gene.

Associated Publicatons to Date:

Chao H, Anthonymuthu TS, Kenny EM, Amoscato AA, Cole LK, Hatch GM, Ji J, Kagan VE, Bayır H. Disentangling oxidation/hydrolysis reactions of brain mitochondrial cardiolipins in pathogenesis of traumatic injury. JCI Insight. 2018 Nov 2;3(21). pii: 97677. doi: 10.1172/jci.insight.97677. [Epub ahead of print] (PubMed – Open Access)*

Cole LK, Kim JH, Amoscato AA, Tyurina YY, Bayir H, Karimi B, Siddiqui TJ, Kagan VE, Hatch GM, Kauppinen TM. Aberrant cardiolipin metabolism is associated with cognitive deficiency and hippocampal alteration in tafazzin knockdown mice. Biochim Biophys Acta. 2018 Jul 25. pii: S0925-4439(18)30271-0. doi: 10.1016/j.bbadis.2018.07.022. [Epub ahead of print] (PubMed Abstract)*

Kagan VE, Bayır H, Tyurina YY, Bolevich SB, Maguire JJ, Fadeel B, Balasubramanian K. Elimination of the unnecessary: Intra- and extracellular signaling by anionic phospholipids. Review Article. Biochemical and Biophysical Research Communications, Volume 482, Issue 3, 15 January 2017, Pages 482-490. (PubMed Abstract)*

Tyurina YY, Lou W, Qu F, Tyurin VA, Mohammadyani D, Liu J, Hüttemann M, Frasso MA, Wipf P, Bayir H, Greenberg ML, Kagan VE. Lipidomics characterization of biosynthetic and remodeling pathways of cardiolipins in genetically and nutritionally manipulated yeast cells. ACS Chem Biol. 2016 Dec 16. [Epub ahead of print] (PubMed Abstract)*

Kooijman EE, Swim LA, Graber ZT, Tyurina YY, Bayir H, Kagan VE. Magic angle spinning 31P NMR spectroscopy reveals two essentially identical ionization states for the cardiolipin phosphates in phospholipid liposomes. Biochim Biophys Acta. 2016 Oct 26. pii: S0005-2736(16)30346-7. doi:10.1016/j.bbamem.2016.10.013. [Epub ahead of print] (PubMed Abstract)*

Maguire JJ, Tyurina YY, Mohammadyani D, Kapralov AA, Anthonymuthu TS, Qu F, Amoscato AA, Sparvero LJ, Tyurin VA, Planas-Iglesias J, He RR, Klein-Seetharaman J, Bayır H, Kagan VE. Known unknowns of cardiolipin signaling: The best is yet to come. Biochim Biophys Acta. 2016 Aug 4. pii: S1388-1981(16)30221-9. doi: 10.1016/j.bbalip.2016.08.001. [Epub ahead of print] (PubMed Abstract)*

Associated Presentations to Date:

BSF 2016 Conference - July 22, 2016

Multitasking by cardiolipins – intra- and extra-mitochondrial events

BSF 2014 Conference - June 26, 2014

Rancid radical talk: Music of mitochondrial cardiolipins