PUBLICATION
Gremlin1 repression-mediated mitochondrial network hyperfunction contributes to TCE-induced zebrafish cardiac defects
- Authors
- Deng, H., Bai, Z., Huangfu, C., Wang, N., Chen, M., Li, G., Huang, C., Ao, T., Tang, X., Xia, T., Zhang, L., Shen, P., Zhou, W., Gao, Y.
- ID
- ZDB-PUB-250702-23
- Date
- 2025
- Source
- Cell communication and signaling : CCS 23: 318318 (Journal)
- Registered Authors
- Keywords
- Cardiac defects, Gremlin1, Mitochondrial hyperfunction, Single-cell RNA sequencing, Trichloroethylene
- Datasets
- GEO:GSE254184
- MeSH Terms
-
- Animals
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Zebrafish*/embryology
- Trichloroethylene*/toxicity
- Heart Defects, Congenital*/chemically induced
- Heart Defects, Congenital*/genetics
- Heart Defects, Congenital*/metabolism
- Heart Defects, Congenital*/pathology
- Intercellular Signaling Peptides and Proteins*/genetics
- Intercellular Signaling Peptides and Proteins*/metabolism
- Mitochondria*/drug effects
- Mitochondria*/metabolism
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- PubMed
- 40597303 Full text @ Cell Commun. Signal.
Citation
Deng, H., Bai, Z., Huangfu, C., Wang, N., Chen, M., Li, G., Huang, C., Ao, T., Tang, X., Xia, T., Zhang, L., Shen, P., Zhou, W., Gao, Y. (2025) Gremlin1 repression-mediated mitochondrial network hyperfunction contributes to TCE-induced zebrafish cardiac defects. Cell communication and signaling : CCS. 23:318318.
Abstract
Background Trichloroethylene (TCE) is a ubiquitous pollutant with potential capacity to induce congenital heart disease (CHD). However, the mechanisms underlying TCE-induced CHD are largely unraveled.
Methods We exposed zebrafish embryos to TCE to investigate its cardiac development toxicity and related response factor through bulk RNA sequencing. We constructed transgenic fluorescent fish and employed the CRISPR/dCas9 system along with single-cell RNA sequencing to identify the genetic cause of TCE-induced CHD.
Results We found that early-stage exposure to TCE induced significant cardiac defects characterized by elongated SV-BA distance, thinned myocardium, and attenuated contractility. Gremlin1 encoding gene, grem1a, a putative target showing high expression at the beginning of cardiac development, was sharply down-regulated by TCE. Consistently, grem1a knockdown in zebrafish induced cardiac phenotypes generally like those of the TCE-treated group, accompanying the disarrangement of myofibril structure. Single-cell RNA-seq depicted that mitochondrial respiration in grem1a-repressed cardiomyocytes was greatly enhanced, ultimately leading to a branch from the normal trajectory of myocardial development. Accordingly, in vitro results demonstrated that GREM1 repression increased mitochondrial content, ATP production, mitochondrial reactive oxygen species, mitochondrial membrane potential, and disrupted myofibril expansion in hPSC-CMs.
Conclusions These results suggested that TCE-induced gremlin1 repression could result in mitochondrial hyperfunction, thereby hampering cardiomyocyte development and causing cardiac defects in zebrafish embryos. This study not only provided a novel insight into the etiology for environmental stressor-caused cardiac development defects, but also offered a potential therapeutic and preventive target for TCE-induced CHD.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping