Molecular mechanisms underlying a causative role ALCAT1 in the pathogenesis of Barth syndrome
Yuguang (Roger) Shi, PhD, Professor, University of Texas Health Sciences Center in San Antonio, San Antonio, TX

Award - US $100,000 over 3-year period

Abstract:

The onset of Barth syndrome (BTHS) is associated with depletion of tetralinoleoyl cardiolipin (TLCL) and dilated cardiomyopathy. However, molecular mechanisms underlying a causative role of TLCL depletion in cardiomyopathy in BTHS remains poorly understood. To identify novel drug targets for the treatment of BTHS, we have recently generated transgenic mice with targeted deletion of ALCAT1 and inducible deletion of TAZ (TAZDN/ALCAT1-/-) to test our hypothesis that targeted deletion of ALCAT1 will mitigate cardiomyopathy by preventing mitochondrial dysfunction. ALCAT1 is a lysocardiolipin acyltransferase previously identified in this lab. The enzyme catalyzes pathological remodeling of cardiolipin (CL) with fatty acids that are highly sensitive to lipid peroxidation. In support for this hypothesis, ALCAT1 is induced by oxidative stress and the onset of BTHS. Overexpression of ALCAT1 in cardiac cell lines leads to multiple metabolic defects that are reminiscent of those in BTHS, including TLCL depletion, oxidative stress, and mitochondrial dysfunction. Using the TAZDN/ALCAT1-/- mice and the related controls, we demonstrated in this study that targeted deletion of ALCAT1 in mice prevents the onset of dilated cardiomyopathy. Additionally, we show that TAZ depletion caused mitochondrial dysfunction in part by impairing mitochondrial autophagy (mitophagy), leading to oxidative stress, accumulation of dysfunctional mitochondria, and impaired oxidative phosphorylation. Strikingly, these defects are mitigated by ALCAT1 deficiency. ALCAT1 deficiency also restored mitophagy, leading to a significant increase in mtDNA copy number and capacity of mitochondrial oxidative phosphorylation in TAZDN/ALCAT1-/- mice. Consistent with previous reports, TAZ deficiency also caused depletion of TLCL concurrently with increased levels of lysocardiolipin. Surprisingly, these defects were not mitigated by ALCAT1 deficiency, implicating a novel mechanism(s) by which TAZ deficiency causes cardiomyopathy. Together our findings have validated ALCAT1 as a potential drug target for the treatment of BTHS.