Enhanced Parkin-mediated mitophagy mitigates adverse left ventricular remodelling after myocardial infarction: role of PR-364.

Return to Grants

Publication Year:
2025
Authors:
Lizhuo Ai, Juliana de Freitas Germano, Chengqun Huang, Marianne Aniag, Savannah Sawaged, Jon Sin, Reetu Thakur, Deepika Rai, Christopher Rainville, David E Sterner, Yang Song, Honit Piplani, Suresh Kumar, Tauseef R Butt, Robert M Mentzer, Aleksandr Stotland, Roberta A Gottlieb, Jennifer E Van Eyk
PubMed ID:
39601359
Funding Grants:
Public Summary:
After a heart attack, many patients develop heart failure partly because damaged mitochondria (the cell’s energy factories) build up in the heart. This study tested a new drug called PR-364 that activates a protein named Parkin, which helps clear out damaged mitochondria. Given shortly after a heart attack, PR-364 helped improve survival, protect heart function, and slow heart failure in mice. Lab tests showed the drug boosted the cleaning and rebuilding of mitochondria, improved energy production, and changed how heart cells manage calcium and protein production. Overall, this research suggests PR-364 could be a promising treatment to help protect the heart after a heart attack and prevent heart failure.
Scientific Abstract:
BACKGROUND AND AIMS: Almost 30% of survivors of myocardial infarction (MI) develop heart failure (HF), in part due to damage caused by the accumulation of dysfunctional mitochondria. Organelle quality control through Parkin-mediated mitochondrial autophagy (mitophagy) is known to play a role in mediating protection against HF damage post-ischaemic injury and remodelling of the subsequent deteriorated myocardium. METHODS: This study has shown that a single i.p. dose (2 h post-MI) of the selective small molecule Parkin activator PR-364 reduced mortality, preserved cardiac ejection fraction, and mitigated the progression of HF. To reveal the mechanism of PR-364, a multi-omic strategy was deployed in combination with classical functional assays using in vivo MI and in vitro cardiomyocyte models. RESULTS: In vitro cell data indicated that Parkin activation by PR-364 increased mitophagy and mitochondrial biogenesis, enhanced adenosine triphosphate production via improved citric acid cycle, altered accumulation of calcium localization to the mitochondria, and initiated translational reprogramming with increased expression of mitochondrial translational proteins. In mice, PR-364 administered post-MI resulted in widespread proteome changes, indicating an up-regulation of mitochondrial metabolism and mitochondrial translation in the surviving myocardium. CONCLUSIONS: This study demonstrates the therapeutic potential of targeting Parkin-mediated mitophagy using PR-364 to protect surviving cardiac tissue post-MI from progression to HF.