Georgakopoulos, N D and Frison, M and Alvarez, M S and Bertrand, H and Wells, G and Campanella, M (2017) Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy. Scientific Reports (Nature), 7. p. 10303.
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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.
| Item Type: | Article |
|---|---|
| RVC Publication Type: | Research (full) paper |
| WoS ID: | 000408997700002 |
| DOI: | https://doi.org/10.1038/s41598-017-07679-7 |
| Departments: | Comparative Biomedical Sciences |
| Research Programmes: | Comparative Physiology & Medicine > Immune Regulation and Cancer |
| Depositing User: | RVC Auto-import |
| Last Modified: | 21 Nov 2020 01:56 |
| URI: | https://researchonline.rvc.ac.uk/id/eprint/10963 |
| Date Deposited: | 22 September 2017 |
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