SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy-Reference-Cited by-同舟云学术

SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy

Published:2024-08-20 Issue:8 Volume:150 Page:622-641
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Kovilakath Anna¹^ORCID,Mauro Adolfo G.²^ORCID,Valentine Yolander A.³⁴^ORCID,Raucci Frank J.⁵,Jamil Maryam¹^ORCID,Carter Christiane⁶^ORCID,Thompson Jeremy²,Chen Qun²^ORCID,Beutner Gisela⁷^ORCID,Yue Yang⁴,Allegood Jeremy⁴^ORCID,Wang Xiaoxin X.⁸^ORCID,Dail Jordan⁴,Devarakonda Teja⁹²,Myakala Komuraiah⁸^ORCID,Windle Jolene J.¹¹⁰^ORCID,Subler Mark A.¹,Montefusco David⁴^ORCID,Willard Belinda¹¹^ORCID,Javaheri Ali¹²¹³^ORCID,Bernas Tytus¹⁴^ORCID,Mahata Sushil K.¹⁵^ORCID,Levi Moshe⁸^ORCID,Liu Jinze⁶¹⁰^ORCID,Porter George A.⁷¹⁶¹⁷^ORCID,Lesnefsky Edward J.⁴⁹²¹⁸,Salloum Fadi N.⁹¹⁰²^ORCID,Cowart L. Ashley⁴¹⁰¹⁸^ORCID

Affiliation:

1. Department of Human and Molecular Genetics (A.K., M.J., J.J.W., M.A.S.), Virginia Commonwealth University, Richmond.

2. Department of Internal Medicine, Division of Cardiology, Pauley Heart Center, Richmond, VA (A.G.M., J.T., Q.C., T.D., E.J.L., F.N.S.).

3. C. Kenneth and Dianne Wright Center for Clinical and Translational Research (Y.A.V.), Virginia Commonwealth University, Richmond.

4. Department of Biochemistry and Molecular Biology (Y.A.V., Y.Y., J.A., J.D., D.M., E.J.L., L.A.C.), Virginia Commonwealth University, Richmond.

5. Department of Pediatrics, Division of Pediatric Cardiology (F.J.R.), Virginia Commonwealth University, Richmond.

6. Bioinformatics Shared Resource, Massey Comprehensive Cancer Center (C.C., J.L.), Virginia Commonwealth University, Richmond.

7. Department of Pediatrics (G.B., G.A.P.), University of Rochester Medical Center, NY.

8. Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC (X.X.W., K.M., M.L.).

9. Department of Physiology and Biophysics (F.N.S., T.D., E.J.L.), Virginia Commonwealth University, Richmond.

10. Massey Comprehensive Cancer Center (J.J.W., J.L., F.N.S., L.A.C.), Virginia Commonwealth University, Richmond.

11. Proteomics and Metabolomics Shared Laboratory Resource, Lerner Research Institute, Cleveland Clinic, OH (B.W.)

12. Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO (A.J.).

13. St. Louis Veterans’ Affairs Medical Center, MO (A.J.).

14. Department of Anatomy and Neurobiology (T.B.), Virginia Commonwealth University, Richmond.

15. Veterans’ Affairs San Diego Healthcare System and University of California San Diego, (S.K.M).

16. Department of Pharmacology and Physiology (G.A.P.), University of Rochester Medical Center, NY.

17. Aab Cardiovascular Research Institute (G.A.P.), University of Rochester Medical Center, NY.

18. Richmond Veterans’ Affairs Medical Center, VA (E.J.L., L.A.C.).

Abstract

BACKGROUND: Dysregulated metabolism of bioactive sphingolipids, including ceramides and sphingosine-1-phosphate, has been implicated in cardiovascular disease, although the specific species, disease contexts, and cellular roles are not completely understood. Sphingolipids are produced by the serine palmitoyltransferase enzyme, canonically composed of 2 subunits, SPTLC1 (serine palmitoyltransferase long chain base subunit 1) and SPTLC2 (serine palmitoyltransferase long chain base subunit 2). Noncanonical sphingolipids are produced by a more recently described subunit, SPTLC3 (serine palmitoyltransferase long chain base subunit 3). METHODS: The noncanonical (d16) and canonical (d18) sphingolipidome profiles in cardiac tissues of patients with end-stage ischemic cardiomyopathy and in mice with ischemic cardiomyopathy were analyzed by targeted lipidomics. Regulation of SPTLC3 by HIF1α under ischemic conditions was determined with chromatin immunoprecipitation. Transcriptomics, lipidomics, metabolomics, echocardiography, mitochondrial electron transport chain, mitochondrial membrane fluidity, and mitochondrial membrane potential were assessed in the cSPTLC3 KO transgenic mice we generated. Furthermore, morphological and functional studies were performed on cSPTLC3 KO mice subjected to permanent nonreperfused myocardial infarction. RESULTS: Herein, we report that SPTLC3 is induced in both human and mouse models of ischemic cardiomyopathy and leads to production of atypical sphingolipids bearing 16-carbon sphingoid bases, resulting in broad changes in cell sphingolipid composition. This induction is in part attributable to transcriptional regulation by HIF1α under ischemic conditions. Furthermore, cardiomyocyte-specific depletion of SPTLC3 in mice attenuates oxidative stress, fibrosis, and hypertrophy in chronic ischemia, and mice demonstrate improved cardiac function and increased survival along with increased ketone and glucose substrate metabolism utilization. Depletion of SPTLC3 mechanistically alters the membrane environment and subunit composition of mitochondrial complex I of the electron transport chain, decreasing its activity. CONCLUSIONS: Our findings suggest a novel essential role for SPTLC3 in electron transport chain function and a contribution to ischemic injury by regulating complex I activity.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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