ML335 inhibits TWIK2 channel-mediated potassium efflux and attenuates mitochondrial damage in MSU crystal-induced inflammation.

J Transl Med

Institute of Rheumatology and Immunology, The Affiliated Hospital of North Sichuan Medical College and Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637001, Sichuan, China.

Published: August 2024

AI Article Synopsis

  • The study examines the role of the TWIK2 channel in gout inflammation and the therapeutic potential of the K2P channel modulator ML335 to inhibit the NLRP3 inflammasome activation.
  • ML335 showed the strongest binding to TWIK2 compared to other tested compounds and effectively reduced the release of the inflammatory marker IL-1β from immune cells.
  • The findings indicate that ML335 improves mitochondrial function and reduces inflammation by suppressing MARCH5 expression, which interacts with SIRT3, thereby enhancing potential treatments for gout-related inflammation.

Article Abstract

Background: Activation of the NLRP3 inflammasome is critical in the inflammatory response to gout. Potassium ion (K) efflux mediated by the TWIK2 channel is an important upstream mechanism for NLRP3 inflammasome activation. Therefore, the TWIK2 channel may be a promising therapeutic target for MSU crystal-induced inflammation. In the present study, we investigated the effect of ML335, a known K2P channel modulator, on MSU crystal-induced inflammatory responses and its underlying molecular mechanisms.

Methods: By molecular docking, we calculated the binding energies and inhibition constants of five K2P channel modulators (Hydroxychloroquine, Fluoxetine, DCPIB, ML365 and ML335) with TWIK2. Intracellular potassium ion concentration and mitochondrial function were assessed by flow cytometry. The interaction between MARCH5 and SIRT3 was demonstrated by immunoprecipitation and Western blotting assay. MSU suspensions were injected into mouse paw and peritoneal cavity to induce acute gout model.

Results: ML335 has the highest binding energy and the lowest inhibition constant with TWIK2 in the five calculated K2P channel modulators. In comparison, among these five compounds, ML335 efficiently inhibited the release of IL-1β from MSU crystal-treated BMDMs. ML335 decreased MSU crystal-induced K efflux mainly dependent on TWIK2 channel. More importantly, ML335 can effectively inhibit the expression of the mitochondrial E3 ubiquitin ligase MARCH5 induced by MSU crystals, and MARCH5 can interact with the SIRT3 protein. ML335 blocked MSU crystal-induced ubiquitination of SIRT3 protein by MARCH5. In addition, ML335 improved mitochondrial dynamics homeostasis and mitochondrial function by inhibiting MARCH5 protein expression. ML335 attenuated the inflammatory response induced by MSU crystals in vivo and in vitro.

Conclusion: Inhibition of TWIK2-mediated K efflux by ML335 alleviated mitochondrial injury via suppressing March5 expression, suggesting that ML335 may be an effective candidate for the future treatment of gout.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342740PMC
http://dx.doi.org/10.1186/s12967-024-05303-7DOI Listing

Publication Analysis

Top Keywords

msu crystal-induced
20
ml335
12
twik2 channel
12
k2p channel
12
msu
9
crystal-induced inflammation
8
nlrp3 inflammasome
8
inflammatory response
8
potassium ion
8
channel modulators
8

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!