Related Experiment Video
Updated: Feb 23, 2026
Protection of H9c2 Myocardial Cells from Oxidative Stress by Crocetin via PINK1/Parkin Pathway-Mediated Mitophagy
Published on: May 26, 2023
Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy
Nikolaos D Georgakopoulos1,2, Michele Frison1, Maria Soledad Alvarez1
1Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, NW1 0TU, London, United Kingdom.
Abstract:
Mitophagy orchestrates the autophagic degradation of dysfunctional mitochondria preventing their pathological accumulation and contributing to cellular homeostasis. We previously identified a novel chemical tool (hereafter referred to as PMI), which drives mitochondria into autophagy without collapsing their membrane potential (ΔΨm). PMI is an inhibitor of the protein-protein interaction (PPI) between the transcription factor Nrf2 and its negative regulator, Keap1 and is able to up-regulate the expression of autophagy-associated proteins, including p62/SQSTM1. Here we show that PMI promotes mitochondrial respiration, leading to a superoxide-dependent activation of mitophagy. Structurally distinct Keap1-Nrf2 PPI inhibitors promote mitochondrial turnover, while covalent Keap1 modifiers, including sulforaphane (SFN) and dimethyl fumarate (DMF), are unable to induce a similar response. Additionally, we demonstrate that SFN reverses the effects of PMI in co-treated cells by reducing the accumulation of p62 in mitochondria and subsequently limiting their autophagic degradation. This study highlights the unique features of Keap1-Nrf2 PPI inhibitors as inducers of mitophagy and their potential as pharmacological agents for the treatment of pathological conditions characterized by impaired mitochondrial quality control.
Insights
Novel mitophagy inducers, PMI, promote mitochondrial health by inhibiting Keap1-Nrf2 interactions. This unique mechanism enhances cellular homeostasis and offers potential therapeutic strategies for mitochondrial disorders.
Area of Science:
- Cell Biology
- Mitochondrial Dynamics
- Autophagy
Background:
- Mitophagy is crucial for removing damaged mitochondria, maintaining cellular homeostasis.
- Dysfunctional mitochondria accumulation is linked to various pathologies.
- We previously identified PMI, a tool inducing mitophagy without affecting mitochondrial membrane potential.
Purpose of the Study:
- To investigate the mechanism by which PMI induces mitophagy.
- To explore the potential of Keap1-Nrf2 protein-protein interaction (PPI) inhibitors as mitophagy inducers.
- To compare the effects of PPI inhibitors with covalent Keap1 modifiers.
Main Methods:
- Utilized PMI, a Keap1-Nrf2 PPI inhibitor.
- Assessed mitochondrial respiration and superoxide production.
- Examined p62/SQSTM1 accumulation in mitochondria.
- Co-treated cells with PMI and sulforaphane (SFN).
Main Results:
- PMI promotes mitochondrial respiration and activates mitophagy in a superoxide-dependent manner.
- Structurally distinct Keap1-Nrf2 PPI inhibitors, unlike covalent modifiers (SFN, DMF), induce mitochondrial turnover.
- SFN counteracts PMI's effects, reducing p62 accumulation and mitophagy.
Conclusions:
- Keap1-Nrf2 PPI inhibitors represent a unique class of mitophagy inducers.
- PMI's mechanism offers a novel approach to enhance mitochondrial quality control.
- These findings suggest potential pharmacological applications for treating diseases with impaired mitophagy.
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
02:34Inhibition of Cdk Activity