Drp1/p53 interaction mediates p53 mitochondrial localization and dysfunction in septic cardiomyopathy
Riddhita Mukherjee1, Laura H Tetri2, Sin-Jin Li3
1Department of Pediatrics, Division of Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Journal of Molecular and Cellular Cardiology
|February 25, 2023
Summary
Dynamin-related protein 1 (Drp1) and p53 interaction drives mitochondrial damage in sepsis-induced myocardial dysfunction (SIMD). Inhibiting this Drp1/p53 interaction protects cardiac function and improves survival in sepsis models.
Area of Science:
- Cardiovascular Research
- Mitochondrial Biology
- Sepsis Pathophysiology
Background:
- Sepsis-induced myocardial dysfunction (SIMD) involves p53-dependent mitochondrial issues.
- Mechanisms of p53 mitochondrial translocation in SIMD remain unclear.
- Dynamin-related protein 1 (Drp1) mediates mitochondrial fission and may influence p53 localization.
Purpose of the Study:
- To investigate the role of Drp1/p53 interaction in SIMD.
- To elucidate the impact of this interaction on mitochondrial function and cardiac health.
Main Methods:
- Utilized in vitro (H9c2 cardiomyoblasts) and in vivo (BALB/c mice) sepsis models induced by lipopolysaccharide (LPS).
- Employed pharmacologic inhibitors of Drp1 activation (ψDrp1) and p53 mitochondrial binding (pifithrin μ, PFTμ).
- Assessed Drp1/p53 interaction, mitochondrial morphology, function, oxidative stress, and cardiac performance.
Main Results:
- LPS increased Drp1/p53 interaction, leading to p53 mitochondrial localization and dysfunction in both models.
- Inhibition of Drp1/p53 interaction with ψDrp1 or PFTμ reduced mitochondrial p53 import, oxidative stress, and improved cellular respiration and ATP production.
- Treatments improved cardiomyocyte function and survival in mice, reducing cardiac mitochondrial reactive oxygen species (ROS).
Conclusions:
- Drp1/p53 interaction is a critical early event in mitochondrial damage in SIMD.
- Targeting the Drp1/p53 interaction presents a potential therapeutic strategy for SIMD.
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