ALCAT1 as a Novel Target for the Treatment of Cardiomyopathy in Barth Syndrome
Jun Zhang PhD, University of Texas Health Science Center at San Antonio
Barth syndrome (BTHS) is an X-linked genetic disorder caused by mutations in the tafazzin (TAZ) gene. TAZ encodes a mitochondrial transacylase that catalyzes the remodeling of cardiolipin (CL), a mitochondrial signature phospholipid that is required for mitochondrial membrane structure, dynamics, biogenesis, mitophagy, apoptosis, and inflammation. TAZ mutations in BTHS cause depletion of tetralinoleoyl CL (TLCL), leading to oxidative stress, mitochondrial dysfunction, dilated cardiomyopathy, and premature death. Currently, there is no effective treatment for this lethal condition, because the underlying causes for the pathogenesis remain elusive. In this study, we will evaluate Acyl-CoA:lysocardiolipin Acyltransferase 1 (ALCAT1) as a drug target for the treatment of cardiomyopathy in BTHS. ALCAT1 is an acyl-CoA lysocardiolipin acyltransferase that catalyzes the reacylation of lysocardiolipin to CL. Our previous studies show that ALCAT1 catalyzes the pathological remodeling of CL with aberrant fatty acyl chains that enriched with polyunsaturated fatty acids (PUFA). Enrichment of PUFA renders CL highly sensitive to oxidative damage by reactive oxygen species (ROS), leading to CL depletion, mitochondrial DNA (mtDNA) release and mitochondrial dysfunction. Consequently, overexpression of ALCAT1 in cultured cardiomyocytes leads to multiple metabolic defects that are reminiscent of those in BTHS, including TLCL depletion, oxidative stress, defective mitophagy, and mitochondrial dysfunction. In contrast, our preliminary data show that ablation of ALCAT1 mitigates cardiomyopathy and left ventricular dysfunction in TAZ knockdown mice, a mouse model of BTHS, by restoring mitochondrial function, implicating ALCAT1 as a potential target for the treatment of BTHS. In this study, using the TAZ knockdown mice, as well as the TAZ deficient cardiomyocytes and mouse embryonic fibroblasts with target deletion of ALCAT1, we will determine whether ALCAT1-mediated oxidative stress, mtDNA instability, or defective mitophagy contribute to mitochondrial dysfunction in BTHS. Additionally, we have recently developed and completed an in vitro high-throughput screening assay to identify small molecule inhibitors of ALCAT1, and successfully identified several potent and specific ALCAT1 inhibitors, one of which is Dafaglitapin (Dafa). Our recent work showed that inhibition of ALCAT1 by Dafa significantly improves cardiac function in mice with myocardial infarction. In this study, we will assess whether pharmacological inhibition of ALCAT1 by Dafa will attenuate cardiomyopathy in TAZ knockdown mice. The completion of the proposed studies is expected to provide key insights on mitochondrial dysfunction by ALCAT1 on the pathogenesis of cardiomyopathy in BTHS, which will lay a foundation to develop a potential and effective treatment for cardiomyopathy in BTHS by inhibition of ALCAT1 with small molecule inhibitors.