Drp1/p53 interaction plays a key role in mitochondrial dysfunction of septic cardiomyopathy

Introduction: Sepsis-induced myocardial depression (SIMD), a common complication of sepsis, is associated with increased risk of multi-organ system dysfunction and death. Previous studies have implicated p53-dependent mitochondrial dysfunction in sepsis induced end organ injury. However, the mechanisms behind p53 localization to the mitochondria have not been well established in sepsis. Dynamin-related protein 1 (Drp1), a mediator of mitochondrial fission, may play a role in p53 mitochondrial localization. We hypothesized that Drp1 / p53 interact in in vitro and murine models of sepsis to induce p53 mitochondrial localization. Methods: We used H9c2 cardiomyoblasts in vitro and BALB/c mice in vivo exposed to lipopolysaccharide (LPS) to model sepsis phenotype. Pharmacologic inhibitors of Drp1 activation (psi-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 function, cardiomyocyte contractility, and sepsis phenotype. Results: Both in vitro and murine models demonstrated physical Drp1/p53 interaction by co-immunoprecipitation and proximity ligation assay that increased following LPS treatment, which was associated with increased p53 mitochondrial localization, pathologic mitochondrial fission, and increased oxidative stress. This Drp1/p53 interaction was inhibited by psi-Drp1, suggesting that this interaction is dependent on Drp1 activation. Treatment of H9c2 cells with either psi-Drp1 or PFT mu following LPS treatment inhibited the localization of Drp1/p53 to the mitochondria, decreased pathologic mitochondrial fission and oxidative stress and improved cellular respiration and ATP production. Similarly, treatment of BALB/c mice with either psi-Drp1 or PFT mu following LPS treatment decreased mitochondrial localization of p53, mitochondrial oxidative stress in cardiac tissue, improved cardiomyocyte contractile function and relaxation, and survival. Conclusions: Our data demonstrates that Drp1/p53 interaction and mitochondrial localization is key in mitochondrial damage in septic cardiomyopathy. Furthermore, inhibiting Drp1/p53 interaction and mitochondrial localization may serve as a therapeutic target for sepsis-induced mitochondrial damage and end-organ failure.