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AI662270-GRP94 axis couples the unfolded protein response to mitochondrial dynamics during acute myocardial infarction

ABSTRACT: Endoplasmic reticulum stress (ERS) response, triggered by myocardial ischemia, contributes to cardiac injury through unresolved mechanisms. Our study reveals that the chaperone GRP94 attenuates mitochondrial fragmentation and ischemic damage by inhibiting OPA1 hydrolysis to S-OPA1 post-acute myocardial infarction (AMI). Mechanistically, hypoxia induces a transcriptional switch where transcription factor YY1 dissociates from lncRNA Oip5os1 and binds lncRNA AI662270, promoting GRP94 transcription. Cardiac-specific GRP94 overexpression reduced infarct size and improved cardiac function. Conversely, GRP94 or AI662270 knockdown exacerbated injury. Furthermore, GRP94-Anxa2 interaction (identified by Co-IP/MS) activates AKT signaling to stabilize long-form OPA1 (L-OPA1), preserving mitochondrial integrity. Targeting the AI662270/GRP94/OPA1 axis thus offers a novel therapeutic strategy for acute ischemic cardiomyopathy by modulating ER-mitochondria crosstalk.

ORGANISM(S): Mus musculus

PROVIDER: GSE304427 | GEO | 2025/08/13

REPOSITORIES: GEO

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Project description:The management of cardiac ischemic injury has been challenged by ischemia and reperfusion (I/R) injury. Reactive oxygen species (ROS) generated from mitochondrial reverse electron transport (RET) during the early phase of reperfusion is considered to be the initiating cause for ischemia and reperfusion injury. Ginsenosides and their prescriptions are widely used in the clinic for treatment of myocardial ischemia, however, the action to combat ROS remains to be elucidated. In this work, we used TMT-based proteomic approach to detect differential proteins from mitochondrial fractions of mice hearts with ischemia-reperfusion. Results indicated that the mass error of identified peptides was within 10 ppm, and most of the identified peptides were composed of 7-23 amino acids. Using these qualified data, 17,262 peptides, with a confidence level ≥ 95%, were mapped to 3,054 protein groups. PCA analysis showed that the model group was clearly separated from the blank group, while the protein pattern was partly reversed with Rb1 treatment. With a criteria of p-value < 0.05, 591 significantly changed proteins including 186 increased and 405 decreased ones in the model group were identified compared with the blank group. These proteins were divided into 4 clusters. Proteins in Cluster I highly increased in the model group, but clearly decreased in the Rb1 group. Proteins in Cluster IV clearly decreased in the model group, but markedly increased in the Rb1 group. Proteins in Cluster III and in Cluster IV were not significantly or slightly regulated by the Rb1 treatment. GO analysis of Cluster I and II indicated that the molecular function of these proteins were closely related to oxidoreductase activity and NADH dehydrogenase activity. Our result showed that Rb1 administration before ischemia markedly decreased infarct size (48 h post-I/R), and preserved cardiac function (2 weeks post-I/R), and subsequently limited tissue fibrosis (28 days post-I/R). These results indicated that targeted inhibition of mitochondrial complex I in the early stage of reperfusion by Rb1 is a potential therapeutic strategy for alleviating IR injury. This work not only indicates a potent molecular target for the precision therapy of myocardial ischemia by Rb1, but also provides novel knowledge for the management of cardiac ischemic injury by traditional Chinese medicine.

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AI662270-GRP94 axis couples the unfolded protein response to mitochondrial dynamics during acute myocardial infarction

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