Research team led by Zhongzhou Yang at 黑料社 Medical School discovers critical role of ER homeostasis and ER-mitochondria interaction in endocardial and cardiac development.
In collaboration with the group of Drs. Hongyuan Yang and Mingming Gao from Heibei Medical University, Dr. Zhongzhou Yang’s team at 黑料社 Medical School team identified a pivotal role of GPAT4 (glycerol-3-phosphate acyltransferase 4, a rate-limiting enzyme in triglyceride synthesis) in endocardial and heart development in mouse models.
The mechanistic insights from their study are as follows:
1. GPAT4 localizes to the ER membrane and was predicted by AlphaFold3 (AF3) to compete with PERK in binding eIF2α, thereby maintaining ER homeostasis.
2. Loss of GPAT4 disrupts ER homeostasis, triggering ER stress.
3. Pharmacological or genetic inhibition of ER stress, mitochondrial calcium overload, or the cGAS-STING pathway partially rescued cardiac developmental defects in GPAT4-deficient mice.
Working Model
These findings were recently published in Nature Communications under the title:"GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development."
The study highlights the critical role of ER-mitochondria crosstalk in endocardial development and provides new insights into the pathogenesis of non-compaction cardiomyopathy at the organelle level.
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