TY - JOUR
T1 - Cardiolipin remodeling by ALCAT1 links hypoxia to coronary artery disease by promoting mitochondrial dysfunction
AU - Jia, Dandan
AU - Zhang, Jun
AU - Nie, Jia
AU - Andersen, John Paul
AU - Rendon, Samantha
AU - Zheng, Yue
AU - Liu, Xueling
AU - Tian, Zhenjun
AU - Shi, Yuguang
N1 - Funding Information:
The authors would like to thank Dr. Xianlin Han for technical help with lipidomic analysis and Dr. Nicolas Musi for fruitful discussion. This work was supported, in part, by funding from the NIH ( R01AG055747 ; to Y.S.), American Diabetes Association (# 1-18 IBS-329 ; to Y.S.), Barth Syndrome Foundation (to Y.S.), an endowment from Joe R. and Teresa Lozano Long Distinguished Chair in Metabolic Biology (to Y.S.), NIA T32 Training Grant ( T32GM108563 ; to J.-P.A.), and National Natural Science Foundation of China (grant no. 31671240 ; to Z.T.).
Publisher Copyright:
© 2021 The American Society of Gene and Cell Therapy
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
KW - apoptosis
KW - cardiac function
KW - cardiolipin
KW - inflammation
KW - mitochondrial dysfunction
KW - myocardial infarction
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U2 - 10.1016/j.ymthe.2021.06.007
DO - 10.1016/j.ymthe.2021.06.007
M3 - Article
C2 - 34111561
AN - SCOPUS:85114676724
SN - 1525-0016
VL - 29
SP - 3498
EP - 3511
JO - Molecular Therapy
JF - Molecular Therapy
IS - 12
ER -