2. Academic Validation
  3. Cardiolipin remodeling by ALCAT1 links hypoxia to coronary artery disease by promoting mitochondrial dysfunction

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

  • Mol Ther. 2021 Dec 1;29(12):3498-3511. doi: 10.1016/j.ymthe.2021.06.007.
Dandan Jia 1,  Jun Zhang 2,  Jia Nie 3,  John-Paul Andersen 3,  Samantha Rendon 4,  Yue Zheng 5,  Xueling Liu 6,  Zhenjun Tian 7,  Yuguang Shi 8
Affiliations

Affiliations

  • 1 Institute of Sports and Exercise Biology, School of Physical Education, Shaanxi Normal University, Xi'an, Shaanxi 710119, China; Barshop Institute for Longevity and Aging Studies, Department of Pharmacology, University of Texas Health Science Center at San Antonio, 4939 Charles Katz Dr., San Antonio, TX 78229, USA.
  • 2 Barshop Institute for Longevity and Aging Studies, Department of Pharmacology, University of Texas Health Science Center at San Antonio, 4939 Charles Katz Dr., San Antonio, TX 78229, USA; Perenna Pharmaceuticals, Inc., 14785 Omicron Drive, San Antonio, TX 78245, USA.
  • 3 Barshop Institute for Longevity and Aging Studies, Department of Pharmacology, University of Texas Health Science Center at San Antonio, 4939 Charles Katz Dr., San Antonio, TX 78229, USA.
  • 4 Perenna Pharmaceuticals, Inc., 14785 Omicron Drive, San Antonio, TX 78245, USA.
  • 5 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
  • 6 Barshop Institute for Longevity and Aging Studies, Department of Pharmacology, University of Texas Health Science Center at San Antonio, 4939 Charles Katz Dr., San Antonio, TX 78229, USA; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
  • 7 Institute of Sports and Exercise Biology, School of Physical Education, Shaanxi Normal University, Xi'an, Shaanxi 710119, China. Electronic address: tianzhj@snnu.edu.cn.
  • 8 Barshop Institute for Longevity and Aging Studies, Department of Pharmacology, University of Texas Health Science Center at San Antonio, 4939 Charles Katz Dr., San Antonio, TX 78229, USA; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China. Electronic address: shiy4@uthscsa.edu.
PMID: 34111561 DOI: 10.1016/j.ymthe.2021.06.007
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.

Keywords

apoptosis; cardiac function; cardiolipin; inflammation; mitochondrial dysfunction; myocardial infarction.

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