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

cardiomyopathy electron transport complex I mitochondria serine C-palmitoyltransferase sphingolipids

Journal

Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763

Informations de publication

Date de publication:
25 Apr 2024
Historique:
medline: 25 4 2024
pubmed: 25 4 2024
entrez: 25 4 2024
Statut: aheadofprint

Résumé

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). 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 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. 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.

Sections du résumé

BACKGROUND UNASSIGNED
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 UNASSIGNED
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
RESULTS UNASSIGNED
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 UNASSIGNED
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.

Identifiants

DOI: 10.1161/CIRCULATIONAHA.123.066879 PMID: 38660786
pubmed: 38660786
doi: 10.1161/CIRCULATIONAHA.123.066879
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Auteurs

Anna Kovilakath (A)

Department of Human and Molecular Genetics (A.K., M.J., J.J.W., M.A.S.), Virginia Commonwealth University, Richmond.
ORCID: 0000-0003-0735-9131

Adolfo G Mauro (AG)

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.).
ORCID: 0000-0002-5786-5844

Yolander Valentine (Y)

C. Kenneth and Dianne Wright Center for Clinical and Translational Research (Y.V.), Virginia Commonwealth University, Richmond.
Department of Biochemistry and Molecular Biology (Y.V., Y.Y., J.A., J.D., D.M., E.J.L., L.A.C.), Virginia Commonwealth University, Richmond.
ORCID: 0000-0001-8082-7734

Frank Raucci (F)

Department of Pediatrics, Division of Pediatric Cardiology (F.R.), Virginia Commonwealth University, Richmond.
ORCID: 0000-0002-3464-6569

Maryam Jamil (M)

Department of Human and Molecular Genetics (A.K., M.J., J.J.W., M.A.S.), Virginia Commonwealth University, Richmond.
ORCID: 0009-0006-3240-0027

Christiane Carter (C)

Bioinformatics Shared Resource, Massey Comprehensive Cancer Center (C.C., J.L.), Virginia Commonwealth University, Richmond.
ORCID: 0000-0003-4956-7991

Jeremy Thompson (J)

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.).

Qun Chen (Q)

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.).
ORCID: 0000-0001-5683-7844

Beutner Gisela (B)

ORCID: 0000-0002-6157-0934

Yang Yue (Y)

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

Jeremy Allegood (J)

Department of Biochemistry and Molecular Biology (Y.V., Y.Y., J.A., J.D., D.M., E.J.L., L.A.C.), Virginia Commonwealth University, Richmond.
ORCID: 0009-0007-1741-9923

Xiaoxin X Wang (XX)

Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC (X.X.W., K.M., M.L.).
ORCID: 0000-0001-9205-6228

Jordan Dail (J)

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

Teja Devarakonda (T)

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

Komuraiah Myakala (K)

Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC (X.X.W., K.M., M.L.).
ORCID: 0000-0003-3233-047X

Jolene J Windle (JJ)

Department of Human and Molecular Genetics (A.K., M.J., J.J.W., M.A.S.), Virginia Commonwealth University, Richmond.
Massey Comprehensive Cancer Center (J.J.W., J.L., F.N.S., L.A.C.), Virginia Commonwealth University, Richmond.
ORCID: 0000-0001-6690-385X

Mark A Subler (MA)

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

David Montefusco (D)

Department of Biochemistry and Molecular Biology (Y.V., Y.Y., J.A., J.D., D.M., E.J.L., L.A.C.), Virginia Commonwealth University, Richmond.
ORCID: 0000-0003-4217-4378

Belinda Willard (B)

Proteomics and Metabolomics Shared Laboratory Resource, Lerner Research Institute, Cleveland Clinic, OH (B.W.).
ORCID: 0000-0001-6884-6369

Ali Javaheri (A)

Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO (A.J.).
St. Louis Veterans' Affairs Medical Center, MO (A.J.).
ORCID: 0000-0001-6657-331X

Tytus Bernas (T)

Department of Anatomy and Neurobiology (T.B.), Virginia Commonwealth University, Richmond.
ORCID: 0000-0003-0841-5940

Sushil K Mahata (SK)

Veterans' Affairs San Diego Healthcare System and University of California San Diego, (S.K.M).
ORCID: 0000-0002-8300-9873

Moshe Levi (M)

Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC (X.X.W., K.M., M.L.).
ORCID: 0000-0001-6403-2261

Jinze Liu (J)

Bioinformatics Shared Resource, Massey Comprehensive Cancer Center (C.C., J.L.), Virginia Commonwealth University, Richmond.
Massey Comprehensive Cancer Center (J.J.W., J.L., F.N.S., L.A.C.), Virginia Commonwealth University, Richmond.
ORCID: 0000-0003-0555-9412

George A Porter (GA)

Department of Pediatrics (G.B., G.A.P.), University of Rochester Medical Center, NY.
Department of Pharmacology and Physiology (G.A.P.), University of Rochester Medical Center, NY.
Aab Cardiovascular Research Institute (G.A.P.), University of Rochester Medical Center, NY.
ORCID: 0000-0003-0726-9988

Edward J Lesnefsky (EJ)

Department of Biochemistry and Molecular Biology (Y.V., Y.Y., J.A., J.D., D.M., E.J.L., L.A.C.), Virginia Commonwealth University, Richmond.
Department of Physiology and Biophysics (T.D., E.J.L.), Virginia Commonwealth University, Richmond.
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.).
Richmond Veterans' Affairs Medical Center, VA (E.J.L., L.A.C.).

Fadi N Salloum (FN)

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

L Ashley Cowart (LA)

Department of Biochemistry and Molecular Biology (Y.V., Y.Y., J.A., J.D., D.M., E.J.L., L.A.C.), Virginia Commonwealth University, Richmond.
Massey Comprehensive Cancer Center (J.J.W., J.L., F.N.S., L.A.C.), Virginia Commonwealth University, Richmond.
Richmond Veterans' Affairs Medical Center, VA (E.J.L., L.A.C.).
ORCID: 0000-0002-5312-5232

Classifications MeSH