Inhibition of TRPV4 Regulates Mitophagy Through the Sirt1/FoxO1 Signaling Pathway To Alleviate Acute Lung Injury

Area of Science:

• Cell Biology
• Mitochondrial Dynamics
• Autophagy

Background:

• Acute lung injury (ALI) involves calcium dysregulation, with the Transient Receptor Potential Vanilloid 4 (TRPV4) channel implicated.
• The role of TRPV4 in mitophagy and its interaction with the Sirtuin 1 (Sirt1) signaling pathway in ALI are not fully understood.

Purpose of the Study:

• To investigate the role of TRPV4 in mitophagy during lipopolysaccharide (LPS)-induced ALI.
• To elucidate the crosstalk between TRPV4 and the Sirt1/Forkhead box O1 (FoxO1) signaling axis in regulating mitophagy and ALI.

Main Methods:

• In vivo and in vitro models of LPS-induced ALI were used.
• TRPV4 activation and inhibition were achieved using specific agonists (GSK1016790A) and antagonists (GSK2193874), respectively.
• TRPV4 knockout mice and Sirt1 inhibition were employed to assess genetic and pharmacological effects on mitophagy and ALI.

Main Results:

• LPS upregulated TRPV4, oxidative stress, and apoptosis, exacerbating ALI.
• TRPV4 activation impaired mitophagy, evidenced by reduced LC3/TOMM20 co-localization and PINK1/PARK2 expression.
• TRPV4 inhibition or knockout attenuated ALI, enhanced mitophagic flux, and upregulated Sirt1/FoxO1 signaling, promoting mitophagy.
• Sirt1 inhibition reversed the protective effects of TRPV4 inhibition, confirming its role in the TRPV4-mitophagy axis.

Conclusions:

• TRPV4 exacerbates LPS-induced ALI by suppressing Sirt1/FoxO1-mediated mitophagy.
• Genetic or pharmacological inhibition of TRPV4 restores mitophagic clearance of dysfunctional mitochondria.
• The TRPV4-Sirt1/FoxO1 axis represents a novel therapeutic target for septic ALI and critical care settings.