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Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy.

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 (??_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.

SUBMITTER: Georgakopoulos ND

PROVIDER: S-EPMC5583253 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy.

Georgakopoulos Nikolaos D ND Frison Michele M Alvarez Maria Soledad MS Bertrand Hélène H Wells Geoff G Campanella Michelangelo M

Scientific reports 20170904 1

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 (ΔΨ<sub>m</sub>). 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-re ...[more]

PMID: 28871145

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Project description:Artesunate (ART) is a prominent anti-malarial with significant anti-cancer properties. Our previous studies showed that ART enhances lysosomal function and ferritin degradation, which was necessary for its anti-cancer properties. ART targeting to mitochondria also significantly improved its efficacy, but the effect of ART on mitophagy, an important cellular pathway that facilitates the removal of damaged mitochondria, remains unknown. Here, we first observed that ART mainly localizes in the mitochondria and its probe labeling revealed that it binds to a large number of mitochondrial proteins and causes mitochondrial fission. Second, we found that ART treatment leads to autophagy induction and the decrease of mitochondrial proteins. When autophagy is inhibited, the decrease of mitochondrial proteins could be reversed, indicating that the degradation of mitochondrial proteins is through mitophagy. Third, our results showed that ART treatment stabilizes the full-length form of PTEN induced putative kinase 1 (PINK1) on the mitochondria and activates the PINK1-dependent pathway. This in turn leads to the recruitment of Parkin, sequestosome 1 (SQSTM1), ubiquitin and microtubule-associated proteins 1A/1B light chain 3 (LC3) to the mitochondria and culminates in mitophagy. When PINK1 is knocked down, ART-induced mitophagy is markedly suppressed. Finally, we investigated the effect of mitophagy by ART on mitochondrial functions and found that knockdown of PINK1 alters the cellular redox status in ART-treated cells, which is accompanied with a significant decrease in glutathione (GSH) and increase in mitochondrial reactive oxidative species (mROS) and cellular lactate levels. Additionally, knockdown of PINK1 leads to a significant increase of mitochondrial depolarization and more cell apoptosis by ART, suggesting that mitophagy protects from ART-induced cell death. Taken together, our findings reveal the molecular mechanism that ART induces cytoprotective mitophagy through the PINK1-dependent pathway, suggesting that mitophagy inhibition could enhance the anti-cancer activity of ART.

Dataset Information

Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy.

Publications

Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy.

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