BAX pores facilitate mitochondrial DNA release in wasp sting-induced acute kidney injury

Area of Science:

• Cell Biology
• Pathology
• Toxicology

Background:

• Mitochondrial dysfunction and DNA release are implicated in acute kidney injury (AKI).
• The precise mechanisms of mitochondrial DNA (mtDNA) leakage in AKI, particularly following venomous stings, require further elucidation.
• B-cell lymphoma 2 (BCL2)-associated X (BAX) protein's role in mitochondrial outer membrane permeabilization is well-established, but its specific involvement in AKI pathogenesis is an active area of research.

Purpose of the Study:

• To investigate the role of BAX-mediated macropore formation in mtDNA leakage during wasp sting-induced AKI.
• To explore the impact of BAX inhibition on mitochondrial integrity, mtDNA release, and downstream inflammatory signaling pathways in AKI models.
• To determine the therapeutic potential of targeting BAX in mitigating kidney damage and dysfunction.

Main Methods:

• Establishment of in vivo (mouse model) and in vitro (human proximal tubular epithelial cells, HK-2) models of wasp sting-induced AKI.
• Assessment of BAX mitochondrial translocation and macropore opening.
• Pharmacological inhibition or genetic knockdown (siRNA) of BAX.
• Measurement of mtDNA release into the cytoplasm using quantitative real-time PCR.
• Evaluation of mitochondrial function, kidney function markers, inflammatory responses, and apoptosis.
• Analysis of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway activation.

Main Results:

• BAX mitochondrial translocation and macropore opening were significantly increased in both in vivo and in vitro AKI models.
• BAX inhibition in mice attenuated mitochondrial impairment, reduced cytoplasmic mtDNA release, and suppressed the mtDNA-cGAS-STING pathway.
• Inhibition of BAX improved kidney function, decreased inflammation, and reduced apoptosis in mouse models of AKI.
• BAX knockdown in HK-2 cells directly demonstrated decreased mtDNA release and ameliorated mitochondrial damage, inflammation, and apoptosis.
• These findings confirm that mtDNA is released via BAX macropores in wasp sting-induced AKI.

Conclusions:

• Mitochondrial DNA (mtDNA) is released into the cytoplasm through BAX-mediated macropores in the context of wasp sting-induced acute kidney injury (AKI).
• Targeting BAX offers a promising therapeutic strategy for managing AKI by preventing mtDNA leakage and subsequent inflammatory cascade activation.
• This study provides a novel perspective on AKI pathogenesis and highlights BAX as a potential therapeutic target for venom-induced organ damage.