title: Ablation of ALCAT1 mitigates hypertrophic cardiomyopathy through effects on oxidative stress and mitophagy.
abstract: Oxidative stress causes mitochondrial dysfunction and  heart failure through unknown mechanisms. Cardiolipin (CL), a mitochondrial membrane phospholipid required for oxidative phosphorylation, plays a pivotal role in cardiac function. The onset of age-related heart diseases is characterized by aberrant CL acyl composition that is highly sensitive to oxidative damage, leading to CL peroxidation and mitochondrial dysfunction. Here we report a key role of ALCAT1, a lysocardiolipin acyltransferase that catalyzes the synthesis of CL with a high peroxidation index, in mitochondrial dysfunction associated with hypertrophic cardiomyopathy. We show that ALCAT1 expression was potently upregulated by the onset of hyperthyroid cardiomyopathy, leading to oxidative stress and mitochondrial dysfunction. Accordingly, overexpression of ALCAT1 in H9c2 cardiac cells caused severe oxidative stress, lipid peroxidation, and mitochondrial DNA (mtDNA) depletion. Conversely, ablation of ALCAT1 prevented the onset of T4-induced cardiomyopathy and cardiac dysfunction. ALCAT1 deficiency also mitigated oxidative stress, insulin resistance, and mitochondrial dysfunction by improving mitochondrial quality control through upregulation of PINK1, a mitochondrial GTPase required for mitochondrial autophagy. Together, these findings implicate a key role of ALCAT1 as the missing link between oxidative stress and mitochondrial dysfunction in the etiology of age-related heart diseases.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Liu
authors.forename: Benlan
authors.initials: B
authors.lastname: Ye
authors.forename: Shane
authors.initials: S
authors.lastname: Miller
authors.forename: Huijuan
authors.initials: H
authors.lastname: Yuan
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Tian
authors.forename: Jia
authors.initials: J
authors.lastname: Nie
authors.forename: Rieko
authors.initials: R
authors.lastname: Imae
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Yuanjian
authors.initials: Y
authors.lastname: Li
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Cheng
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000217:Acyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism*; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy; D018384:Oxidative Stress; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000217:Acyltransferases; D002308:Cardiolipins; D004272:DNA, Mitochondrial; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; D000099202:PTEN-Induced Putative Kinase; C525544:lysocardiolipin acyltransferase, mouse