ArticleCirculation2024
SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy.
Article in Circulation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 2 of them syntheses that pooled it.
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Who cites it
13 citing papers in PubMed, 2 syntheses or guidelines pooled it, 15 citations in OpenAlex.
- Novel Quality Metrics for Assessing the Reproducibility and Translational Relevance of Mouse Transverse Aortic Constriction Experiments: A Systematic Review.Journal of the American Heart Association · 2026Pooled it
- Pathophysiological mechanisms of post-exertional malaise: an integrative analysis based on the metabolism-immune-neuro interaction model.Frontiers in immunology · 2026Pooled it
- Sphingolipids and Atherosclerosis.Current atherosclerosis reports · 2026Review
- Thioredoxin system dysregulation and calpain activation drive myocardial disulfidptosis via pathological disulfide bonds remodeling.Cell death discovery · 2026Article
- Detergents without a drain: the evolutionary logic (and liability) of sphingolipids.Journal of lipid research · 2026Review
- Patterns of lipid profile and genetic variations in South Asians.Cardiovascular diabetology. Endocrinology reports · 2025Review
- Article
- Intricate Regulation of Sphingolipid Biosynthesis: An In-Depth Look Into ORMDL-Mediated Regulation of Serine Palmitoyltransferase.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Ceramides in cardiovascular disease: emerging role as independent risk predictors and novel therapeutic targets.Cardiovascular research · 2025Review
- Serum and plasma sphingolipids as biomarkers of chemotherapy-induced cardiotoxicity in female patients with breast cancer.Journal of lipid research · 2025Article
- Sphingolipid metabolites involved in the pathogenesis of atherosclerosis: perspectives on sphingolipids in atherosclerosis.Cellular & molecular biology letters · 2025Review
- Don't Be Surprised When These Surprise You: Some Infrequently Studied Sphingoid Bases, Metabolites, and Factors That Should Be Kept in Mind During Sphingolipidomic Studies.International journal of molecular sciences · 2025Review
- SPTLC3 regulates plasma membrane sphingolipid composition to facilitate hepatic gluconeogenesis.Cell reports · 2024Article
Corrections and comments
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Authors and funding
28 authors at 8 institutions in 2 countries.
Funding
Abstract
backgroundDysregulated 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).
methodsThe 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
resultsHerein, 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.
conclusionsOur findings suggest a novel essential role for SPTLC3 in electron transport chain function and a contribution to ischemic injury by regulating complex I activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.