Participation of mitoKATP in the activation of the NLRP3 inflammasome

• Grant number: 23/05669-8
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: October 01, 2023
• End date: May 31, 2024
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Lincon Felipe Lima Silva
• Supervisor: Michael Karin
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of California, San Diego (UC San Diego), United States
• Associated to the scholarship: 20/08238-0 - Participation of potassium channels and mitochondrial dynamics of macrophages in the pathophysiology of Atherosclerosis, BP.DR

Abstract

Activation of the NLRP3 inflammasome follows a "two-step" route: priming and activation. It has been a consensus that the activation step involves a greater efflux of K+, however the mechanism by which the efflux of K+ induces the activation of the inflammasome is not clear yet. Recent studies have shown the essential role of mitochondrial stress in leaking ox-mtDNA into the cytoplasm to activate NLRP3. Mitochondrial stress, nevertheless, is largely regulated by the potassium cycle in this organelle, which affects ATP synthesis, ROS generation, and calcium influx. The ability of the ATP-blocked potassium channel (mitoKATP) to block the opening of the permeability transition pore (PTP) has already been demonstrated in cardiomyocytes. New studies have revealed that mitoKATP is one of the main potassium channels that participate in the mitochondrial potassium cycle, which makes it reasonable to assume that its malfunction or blockage results in mitochondrial stress. It is possible that one potential contributor to the "second signal" for NLRP3 activation is a decreased influx of mitochondrial K+ through mitoKATP, thus the increased efflux of potassium from the cell induced by NLRP3 activators such as ATP or nigericin merely impairs the proper influx of potassium in the mitochondria. This study aims to evaluate the activation of the NLRP3 inflammasome through leakage of ox-mtDNA in knockdown macrophages to the mitoKATP channel. (AU)