Cardiolipin remodeling by ALCAT1 links hypoxia to coronary artery disease by promoting mitochondrial dysfunction

Dandan Jia, Jun Zhang, Jia Nie, John Paul Andersen, Samantha Rendon, Yue Zheng, Xueling Liu, Zhenjun Tian, Yuguang Shi

Research output: Contribution to journalArticlepeer-review

Abstract

Cardiolipin is a mitochondrial signature phospholipid that plays a pivotal role in maintaining cardiac health. A loss of tetralinoleoyl cardiolipin (TLCL), the predominant cardiolipin species in the healthy mammalian heart, is implicated in the pathogenesis of coronary heart disease (CHD) through poorly defined mechanisms. Here, we identified acyl-coenzyme A:lysocardiolipin acyltransferase-1 (ALCAT1) as the missing link between hypoxia and CHD in an animal model of myocardial infarction (MI). ALCAT1 is an acyltransferase that promotes mitochondrial dysfunction in aging-related diseases by catalyzing pathological remodeling of cardiolipin. In support of a causative role of ALCAT1 in CHD, we showed that ALCAT1 expression was potently upregulated by MI, linking myocardial hypoxia to oxidative stress, TLCL depletion, and mitochondrial dysfunction. Accordingly, ablation of the ALCAT1 gene or pharmacological inhibition of the ALCAT1 enzyme by Dafaglitapin (Dafa), a potent and highly specific ALCAT1 inhibitor, not only restored TLCL levels but also mitochondrial respiration by attenuating signal transduction pathways mediated by hypoxia-inducible factor 1α (HIF-1α). Consequently, ablation or pharmacological inhibition of ALCAT1 by Dafa effectively mitigated CHD and its underlying pathogenesis, including dilated cardiomyopathy, left ventricle dysfunction, myocardial inflammation, fibrosis, and apoptosis. Together, the findings have provided the first proof-of-concept studies for targeting ALCAT1 as an effective treatment for CHD.

Original languageEnglish (US)
Pages (from-to)3498-3511
Number of pages14
JournalMolecular Therapy
Volume29
Issue number12
DOIs
StatePublished - Dec 1 2021

Keywords

  • apoptosis
  • cardiac function
  • cardiolipin
  • inflammation
  • mitochondrial dysfunction
  • myocardial infarction

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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