NOX4-TIM23 interaction regulates NOX4 mitochondrial import and metabolic reprogramming

Area of Science:

• Cell Biology
• Pulmonary Medicine
• Mitochondrial Biology

Background:

• Pulmonary fibrosis is a progressive lung disease.
• Macrophage activation is a key feature of fibrosis.
• Nicotinamide adenine dinucleotide phosphate hydrogen oxidase 4 (NOX4) in macrophages contributes to fibrosis via mitochondrial reactive oxygen species (ROS).

Purpose of the Study:

• To elucidate the mechanism of NOX4 mitochondrial localization during fibrosis.
• To investigate the role of TIM23 in NOX4-mediated mitochondrial effects.

Main Methods:

• Studied asbestos-induced pulmonary fibrosis in lung macrophages.
• Investigated the interaction between NOX4 and TIM23 using human and mouse models.
• Assessed mitochondrial ROS production and metabolic reprogramming.

Main Results:

• NOX4 localized to the mitochondrial matrix in lung macrophages after asbestos exposure through direct interaction with TIM23.
• This interaction was observed in human asbestosis macrophages but not in NOX4-deficient mice.
• TIM23 binding augmented NOX4-induced mitochondrial ROS and shifted macrophage metabolism towards oxidative phosphorylation.

Conclusions:

• The mitochondrial translocase TIM23 directly interacts with NOX4 in lung macrophages.
• This interaction is crucial for NOX4-mediated mitochondrial ROS generation and metabolic reprogramming in pulmonary fibrosis.
• Targeting the TIM23-NOX4 interaction may offer therapeutic strategies for pulmonary fibrosis.