PUBLICATION
WASHC3 knockout disrupts mitochondrial protein homeostasis and energy metabolism in cardiomyocytes
- Authors
- Kim, S., Park, D.D., Glazier, A., Rottbauer, W., Just, S.
- ID
- ZDB-PUB-260303-3
- Date
- 2026
- Source
- Frontiers in cardiovascular medicine 13: 16823811682381 (Journal)
- Registered Authors
- Just, Steffen, Park, Deung-Dae, Rottbauer, Wolfgang
- Keywords
- WASH complex, WASHC3, mitochondrial function, proteomics, zebrafish
- MeSH Terms
- none
- PubMed
- 41768586 Full text @ Front Cardiovasc Med
Citation
Kim, S., Park, D.D., Glazier, A., Rottbauer, W., Just, S. (2026) WASHC3 knockout disrupts mitochondrial protein homeostasis and energy metabolism in cardiomyocytes. Frontiers in cardiovascular medicine. 13:16823811682381.
Abstract
Introduction The WASH complex regulates endosomal actin dynamics and vesicular trafficking and is essential for neuronal integrity and motor function. Although variants in WASHC4, WASHC5, and WASHC3 are linked to neurodevelopmental abnormalities, the role of WASHC3 beyond the nervous system, particularly in cardiac mitochondrial regulation, remains unclear.
Methods We modeled WASHC3 loss of function in zebrafish and human cardiomyocytes. Washc3 was suppressed in zebrafish embryos by antisense oligonucleotide-mediated knockdown, and a stable Washc3 knockout line was generated using CRISPR/Cas9. Washc3-deficient zebrafish hearts were analyzed by quantitative LC-MS/MS proteomics with GO/KEGG enrichment and transcript-level assays. Mitochondrial bioenergetics was assessed by Seahorse XF assays in primary zebrafish cardiomyocytes and in human AC16 cardiomyocytes following AAV-shRNA-mediated WASHC3 knockdown.
Results Washc3 knockdown embryos exhibited neuromuscular degeneration, impaired locomotion, and early cardiac dysfunction. In contrast, Washc3 knockout zebrafish showed normal early development but developed progressive pericardial degeneration and epicardial remodeling in aged animals. Cardiac proteomics revealed downregulation of mitochondrial proteins, particularly oxidative phosphorylation components, supported by pathway enrichment and concordant transcript-level findings. Mitochondrial respiration was significantly impaired in both Washc3-deficient zebrafish cardiomyocytes and WASHC3-depleted human AC16 cardiomyocytes.
Discussion These findings identify a previously unrecognized role for WASHC3 in maintaining cardiac mitochondrial protein homeostasis and bioenergetic function and provide a framework linking neuromuscular and cardiac phenotypes to impaired mitochondrial bioenergetics in energy-demanding tissues.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping