Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-07679-7
Keywords
-
Categories
Funding
- Biotechnology and Biological Sciences Research Council [BB/M010384/1, BB/N007042/1]
- Medical Research Council [G1100809/2]
- Bloomsbury Colleges Consortium PhD Studentship Scheme
- Petplan Charitable Trust
- Umberto Veronesi Foundation
- Marie Curie Actions
- LAM-Bighi Grant Initiative
- Cancer Research UK [C9344/A10268]
- BBSRC [BB/L01923X/1]
- UCL School of Pharmacy
- Biotechnology and Biological Sciences Research Council [1350983, BB/L01923X/1, BB/N007042/1] Funding Source: researchfish
- Cancer Research UK [10268] Funding Source: researchfish
- BBSRC [BB/L01923X/1, BB/N007042/1] Funding Source: UKRI
Ask authors/readers for more resources
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 (Delta Psi(m)). 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available