Drp1/p53 interaction mediates p53 mitochondrial localization and dysfunction in septic cardiomyopathy

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 (i mu Drp1) and of p53 mitochondrial binding (pifithrin mu, PFT mu) 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 41Drp1, suggesting that this interaction is dependent on Drp1 activation. Treatment of H9c2 cells with either 41Drp1 or PFT mu 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 41Drp1 or PFT mu decreased LPS-mediated mitochondrial locali-zation 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.

Automated summary

This study investigates the role of Drp1/p53 interaction in sepsis-induced myocardial dysfunction (SIMD). The results show that there is an increase in Drp1/p53 interaction following LPS treatment, leading to p53 localization to the mitochondria and mitochondrial dysfunction. Inhibiting the Drp1/p53 interaction can improve mitochondrial damage in SIMD.