AMPK/Drp1 pathway mediates Streptococcus uberis-Induced mitochondrial dysfunction
Yuanyuan Zhou1, Ming Li1, Zhenglei Wang1
1MOE Joint International Research Laboratory of Animal Health and Food Safety, Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
International Immunopharmacology
|December 3, 2022
Summary
Streptococcus uberis infection disrupts mitochondrial dynamics in mammary cells, increasing reactive oxygen species (ROS). AMPK activation protects mitochondria by inhibiting Drp1, mitigating oxidative stress during mastitis.
Area of Science:
- Cell Biology
- Biochemistry
- Microbiology
Background:
- Mitochondrial dysfunction and excessive reactive oxygen species (ROS) production contribute to oxidative stress and disease progression.
- Mitochondria are a primary source of ROS, and their impaired function is linked to increased ROS levels.
- Streptococcus uberis is a significant pathogen causing mastitis, impacting mammary epithelial cells.
Purpose of the Study:
- To investigate the role of mitochondrial dynamics and the AMPK/Drp1 pathway in S. uberis-induced mastitis.
- To determine how S. uberis infection affects mitochondrial function and ROS production in mammary epithelial cells.
- To evaluate the therapeutic potential of AMPK activation in mitigating mitochondrial dysfunction during S. uberis infection.
Main Methods:
- Analysis of mitochondrial apoptotic pathway enzymes and mitochondrial function proteins in S. uberis-stimulated mammary epithelial cells.
- Assessment of Drp1 (dynamin-related protein 1) activation, translocation, and its impact on mitochondrial dynamics (fragmentation, Mfn1/Fis1 expression).
- Evaluation of mitochondrial ROS (mROS) levels, membrane potential, and oxidative injury markers.
- Investigation of the effects of AICAR (AMPK activator) and Mdivi-1 (Drp1 inhibitor) on mitochondrial function and S. uberis-induced cellular damage.
Main Results:
- S. uberis infection upregulated pro-apoptotic proteins and downregulated mitochondrial function proteins.
- Drp1 activation and translocation to mitochondria were observed, leading to mitochondrial fragmentation, decreased membrane potential, elevated mROS, and oxidative injury.
- AICAR treatment inhibited Drp1 phosphorylation and mitochondrial translocation, preserving mitochondrial function in an AMPK/Drp1-dependent manner.
- AICAR demonstrated similar protective effects to the Drp1 inhibitor Mdivi-1.
Conclusions:
- S. uberis infection disrupts the balance of mitochondrial dynamics, causing fragmentation and oxidative stress.
- AMP-activated protein kinase (AMPK) acts as an upstream negative regulator of Drp1, ameliorating S. uberis-induced mitochondrial dysfunction.
- Targeting the AMPK/Drp1 pathway presents a potential therapeutic strategy for managing mastitis-associated oxidative stress.
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