Journal article
Short SCN5A Transcript Yields a NaV1.5 Fragment Influencing Cardiac Metabolism
Circulation research, Vol.138(9), e326973
04/24/2026
DOI: 10.1161/CIRCRESAHA.125.326973
PMCID: PMC13045665
PMID: 41808628
Abstract
BACKGROUND:
SCN5A encodes the cardiac NaV1.5 (voltage-gated Na+ channel), classically known for initiating action potentials and recently implicated in cardiomyocyte metabolism via mitochondrial Na+/Ca2+ exchange. SCN5A variants are linked to arrhythmias and heart failure, but mechanisms controlling SCN5A/NaV1.5 expression and its metabolic interface remain understudied.
METHODS:
We used bioinformatic approaches to identify novel SCN5A regulatory features and discovered an alternative polyadenylation (APA) signal downstream of exon 2, which is conserved in humans and several other species but not mice. To test its function, we generated knock-in mice harboring the human APA signal. Western blotting, cell fractionation, and fluorescence microscopy were used to characterize the resulting truncated protein isoform that localizes to mitochondria. Mitochondrial functions and metabolites were assessed in neonatal rat cardiomyocytes, human-induced pluripotent stem cell–derived cardiomyocytes, and mouse hearts overexpressing the novel isoform.
RESULTS:
We identified a well-conserved APA signal downstream of SCN5A exon 2, yielding a truncated transcript isoform (SCN5A-short). Reanalysis of cardiac APA-seq and mRNA-seq data reveals reduced SCN5A-short expression in failing human hearts. Knock-in of the human APA signal into mice enables expression of SCN5A-short while decreasing full-length SCN5A mRNA. SCN5A-short encodes a novel NaV1.5-NT (N-terminal fragment of NaV1.5) that localizes to the mitochondrial matrix in cardiomyocytes and mouse hearts. Exogenous expression of NaV1.5-NT in cultured cardiomyocytes enhances mitochondrial respiration, ATP production, and mitochondrial ROS while depleting NADH. Native polyacrylamide gel electrophoresis analyses indicate that this coincides with enhanced CI (complex I) activities, as well as context-dependent alterations of CV (complex V) assembly. Moreover, moderate cardiomyocyte-targeted NaV1.5-NT expression in mice was sufficient to rewire the cardiac metabolome, with suggestive evidence of increased fatty acid oxidation.
CONCLUSIONS:
APA-mediated regulation of SCN5A produces a short transcript encoding NaV1.5-NT, a novel mitochondrial-targeted peptide that supports cardiomyocyte metabolism. While the precise molecular mechanisms remain unresolved, these findings highlight an unforeseen alternative pathway for expanding SCN5A-mitochondrial crosstalk, with potential implications for metabolic changes in heart failure and arrhythmias.
Details
- Title: Subtitle
- Short SCN5A Transcript Yields a NaV1.5 Fragment Influencing Cardiac Metabolism
- Creators
- Nathan H Witmer - University of IowaJasmyn M Hoeger - University of IowaJared M McLendon - American Association of Colleges of PharmacyColleen S Stein - University of IowaJin-Young Yoon - Fraternal Order of EaglesLili Wang - Vanderbilt University Medical CenterElena Berezhnaya - Temple UniversityJohn W Elrod - Temple UniversityBjörn C Knollmann - Vanderbilt University Medical CenterBarry L London - Fraternal Order of EaglesRyan L Boudreau - Fraternal Order of Eagles
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.138(9), e326973
- DOI
- 10.1161/CIRCRESAHA.125.326973
- PMID
- 41808628
- PMCID
- PMC13045665
- NLM abbreviation
- Circ Res
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Publisher
- American Heart Association
- Grant note
- University of Iowa Carver College of Medicine (Distinguished Scholars Program) National Institutes of Health (NIH) National Heart, Lung, and Blood Institute: R01-HL144717, R01-HL150557, R35-HL177241, R01-HL163979, R01-HL115955, P01-HL134608, R01-HL172926, R35-HL144980 NIH National Institute of Neurological Disorders and Stroke: R01-NS121379 NIH National Institute of General Medical Sciences: T32-GM067795, T34-GM141143 NIH Office of the Director: S10OD038119 American Heart Association: 20IPA35360150, 25TPA1479503, 20EIA35320226, 19POST34380640, 23CDA1055147, 23CDA1052321 University of Iowa Graduate College University of Iowa Office of Undergraduate Research
This work was supported by the University of Iowa Carver College of Medicine (Distinguished Scholars Program to R.L. Boudreau), the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (grants R01-HL144717, R01-HL150557, and R35-HL177241 to R.L. Boudreau; grants R01-HL163979 and R01-HL115955 to B. London; grants P01-HL134608 and R01-HL172926 to J.W. Elrod; and grant R35-HL144980 to B.C. Knollmann), the NIH National Institute of Neurological Disorders and Stroke (grant R01-NS121379 to J.W. Elrod), the NIH National Institute of General Medical Sciences (grant T32-GM067795 to N.H. Witmer and grant T34-GM141143 to J.M. Hoeger), the NIH Office of the Director (S10OD038119 to the University of Iowa Cardiovascular Phenotyping Core), the American Heart Association (grant 20IPA35360150 to R.L. Boudreau, grant 25TPA1479503 to B. London, grant 20EIA35320226 to J.W. Elrod, grant 23PRE1011277 to N.H. Witmer, grants 19POST34380640 and 23CDA1055147 to J.M. McLendon, and grant 23CDA1052321 to J.-Y. Yoon), the University of Iowa Graduate College (fellowship to N.H. Witmer), and the University of Iowa Office of Undergraduate Research (fellowships to J.M. Hoeger).
- Language
- English
- Electronic publication date
- 03/11/2026
- Date published
- 04/24/2026
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9985146115302771
Metrics
1 Record Views