Multi-omics and functional analyses reveal Plin5-mediated organelle crosstalk as a pivotal regulator of acute myocardial infarction
J Wang, L Lin, Y Z ZouAbstract
Background
Lipid droplet-mitochondria (LD-Mito) crosstalk is a core hub for cellular lipid metabolism and energy homeostasis, and its dysregulation drives acute myocardial infarction (AMI)-induced cardiac remodeling and mitochondrial dysfunction. Perilipin 5 (Plin5), a cardiac-enriched LD-localized protein, maintains organelle physical contact and metabolic balance. However, the molecular mechanism by which Plin5 downregulation reshapes organelle interaction networks to regulate AMI progression and post-infarction remodeling remains unclear.
Purpose
This study investigated the function and mechanism of Plin5 downregulation in AMI via multi-omics and in vivo/in vitro experiments, explored its role in mediating cardiomyocyte LD-Mito crosstalk under ischemia, and identified Plin5 as a potential therapeutic target for AMI by restoring its expression.
Methods
Metabolomic and proteomic analyses were performed on myocardial tissues from AMI C57BL/6J mice to screen Plin5 as a key target related to AMI and LD-Mito crosstalk. AAV-mediated Plin5-overexpressing mice were used to establish the AMI model, with infarct severity evaluated at 3 days post-AMI. Adenovirus-mediated Plin5 overexpression models were constructed in adult/neonatal mouse cardiomyocytes (ACM/NMCM) and HL1 cells to explore Plin5 function under ischemic stress.
Results
Multi-omics identified Plin5 as a core protein associated with AMI and LD-Mito crosstalk, with its expression negatively correlated with AMI severity. Public database analysis confirmed Plin5 downregulation in human AMI cardiomyocytes, linking Plin5 downregulation to AMI pathogenesis. In vivo, Plin5 overexpression reduced AMI infarct size, attenuated ischemic injury and inhibited cardiomyocyte death, and enhanced cardiomyocyte LD-Mito colocalization and contact site integrity. In vitro, Plin5 overexpression alleviated ischemic injury in ACM, NMCM and HL1 cells, reduced ROS production, restored mitochondrial function and ATP levels, normalized lipid metabolism, and maintained lipid and energy homeostasis by improving mitochondrial FAO activity. Mechanistically, Plin5 overexpression strengthened LD-Mito crosstalk to promote lipid substrate transfer for FAO, alleviating mitochondrial lipotoxicity and dysfunction, and ultimately inhibiting cardiomyocyte death to exert cardioprotection against AMI.
Conclusions
Plin5 is a key regulator of AMI, and its downregulation disrupts LD-Mito crosstalk to exacerbate myocardial injury. Plin5 overexpression restores organelle interaction, improves mitochondrial lipid and energy homeostasis, and protects against ischemic cardiomyocyte death, highlighting Plin5 as a promising therapeutic target for AMI.ResearchFlow