Drp1/p53 interaction mediates p53 mitochondrial localization and dysfunction in septic cardiomyopathy
Journal
Journal of Molecular and Cellular Cardiology
Journal Volume
177
Start Page
28
End Page
37
Date Issued
2023-04
Author(s)
Riddhita Mukherjee
Laura H. Tetri
Giovanni Fajardo
Nicolai P. Ostberg
Kaleb B. Tsegay
Kanika Gera
Timothy T. Cornell
Daniel Bernstein
Daria Mochly-Rosen
Bereketeab Haileselassie
Abstract
Background: Previous studies have implicated p53-dependent mitochondrial dysfunction in sepsis induced end organ injury, including sepsis-induced myocardial dysfunction (SIMD). However, the mechanisms behind p53 localization to the mitochondria have not been well established. Dynamin-related protein 1 (Drp1), a mediator of mitochondrial fission, may play a role in p53 mitochondrial localization. Here we examined the role of Drp1/p53 interaction in SIMD using in vitro and murine models of sepsis. Methods: H9c2 cardiomyoblasts and BALB/c mice were exposed to lipopolysaccharide (LPS) to model sepsis phenotype. Pharmacologic inhibitors of Drp1 activation (ψDrp1) and of p53 mitochondrial binding (pifithrin μ, PFTμ) were utilized to assess interaction between Drp1 and p53, and the subsequent downstream impact on mitochondrial morphology and function, cardiomyocyte function, and sepsis phenotype. Results: Both in vitro and murine models demonstrated an increase in physical Drp1/p53 interaction following LPS treatment, which was associated with increased p53 mitochondrial localization, and mitochondrial dysfunction. This Drp1/p53 interaction was inhibited by ΨDrp1, suggesting that this interaction is dependent on Drp1 activation. Treatment of H9c2 cells with either ΨDrp1 or PFTμ inhibited the LPS mediated localization of Drp1/p53 to the mitochondria, decreased oxidative stress, improved cellular respiration and ATP production. Similarly, treatment of BALB/c mice with either ΨDrp1 or PFTμ decreased LPS-mediated mitochondrial localization of p53, mitochondrial ROS in cardiac tissue, and subsequently improved cardiomyocyte contractile function and survival. Conclusion: Drp1/p53 interaction and mitochondrial localization is a key prodrome to mitochondrial damage in SIMD and inhibiting this interaction may serve as a therapeutic target.
Subjects
Bioenergetics
deltaPKC
Isolated cardiomyocyte
Lipopolysaccharide
LPS sepsis model
Mitochondrial dynamics
Mitochondrial fission
Mitochondrial function
Septic cardiomyopathy
SDGs
Type
journal article