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Published on: November 30, 2022
Mitochondria and AMP-activated protein kinase-dependent mechanism of efferocytosis
Shaoning Jiang1, Dae Won Park2, William S Stigler1
1From the Department of Medicine.
Abstract:
Defective clearance of apoptotic cells is frequently associated with perpetuation of inflammatory conditions. Our results show a rapid activation of AMP-activated kinase (AMPK) in macrophages upon exposure to apoptotic cells or lysophosphatidylcholine, a specific phospholipid that is produced and released from dying cells. AMPK activation resulted from inhibition of mitochondrial oxygen consumption and ATP production and further depended on Ca(2+) mobilization and mitochondrial reactive oxygen species generation. Once activated, AMPK increased microtubule synthesis and chemokinesis and provided adaptation to energy demand during tracking and engulfment. Uptake of apoptotic cells was increased in lungs of mice that received lysophosphatidylcholine. Furthermore, inhibition of AMPK diminished clearance of apoptotic thymocytes in vitro and in dexamethasone-treated mice. Taken together, we conclude that the mitochondrial AMPK axis is a sensor and enhancer of tracking and removal of apoptotic cell, processes crucial to resolution of inflammatory conditions and a return to tissue homeostasis.
Insights
AMP-activated kinase (AMPK) activation in macrophages enhances the clearance of apoptotic cells, crucial for resolving inflammation and restoring tissue homeostasis. This mitochondrial AMPK pathway aids in tracking and engulfing dying cells.
Area of Science:
- Cell Biology
- Immunology
- Mitochondrial Biology
Background:
- Defective clearance of apoptotic cells contributes to chronic inflammatory diseases.
- Understanding the molecular mechanisms of efferocytosis is critical for therapeutic interventions.
Purpose of the Study:
- To investigate the role of AMP-activated kinase (AMPK) in the clearance of apoptotic cells.
- To elucidate the signaling pathways involved in AMPK activation during efferocytosis.
Main Methods:
- Macrophages were exposed to apoptotic cells and lysophosphatidylcholine.
- AMPK activation was assessed by measuring mitochondrial function, calcium mobilization, and reactive oxygen species.
- Apoptotic cell uptake was quantified in vitro and in vivo in mouse models.
Main Results:
- Apoptotic cells and lysophosphatidylcholine rapidly activated AMPK in macrophages.
- AMPK activation was dependent on mitochondrial dysfunction, Ca(2+) flux, and mitochondrial ROS.
- Activated AMPK enhanced microtubule synthesis, chemokinesis, and apoptotic cell engulfment.
- Inhibition of AMPK impaired apoptotic cell clearance in vitro and in vivo.
Conclusions:
- The mitochondrial AMPK axis acts as a critical sensor and enhancer for apoptotic cell tracking and removal.
- AMPK-mediated efferocytosis is essential for resolving inflammation and maintaining tissue homeostasis.
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