Na⁺ controls hypoxic signalling by the mitochondrial respiratory chain

Area of Science:

• Mitochondrial biology
• Cellular metabolism
• Redox signaling

Background:

• Mitochondrial oxidative phosphorylation (OXPHOS) is vital for metazoan energy production using oxygen (O2).
• OXPHOS generates reactive oxygen species (ROS) that mediate cellular adaptations, particularly during hypoxia, but the mechanism is unclear.
• While calcium (Ca2+) is a known second messenger, sodium (Na+) has been primarily viewed as a membrane potential mediator.

Purpose of the Study:

• To elucidate the role of Na+ as a second messenger in regulating mitochondrial function and ROS production.
• To investigate the mechanism by which Na+ influences the inner mitochondrial membrane and OXPHOS during hypoxia.

Main Methods:

• Investigated the impact of Na+ on mitochondrial membrane fluidity and ubiquinone mobility.
• Utilized studies involving mitochondrial complex I conformational shifts and the Na+/Ca2+ exchanger.
• Examined the consequences of inhibiting Na+ import on cellular adaptation to hypoxia.

Main Results:

• Na+ acts as a second messenger by modulating inner mitochondrial membrane fluidity.
• Hypoxia induces matrix acidification and Ca2+ release, activating the Na+/Ca2+ exchanger to import Na+ into the matrix.
• Na+ reduces membrane fluidity, impairing ubiquinone mobility between complexes II and III, leading to superoxide production at complex III.

Conclusions:

• Sodium ions (Na+) play a critical role as second messengers in controlling mitochondrial oxidative phosphorylation (OXPHOS) and redox signaling.
• Na+ exerts its function through interaction with phospholipids, altering inner mitochondrial membrane fluidity and impacting cellular metabolism and adaptation.
• The Na+/Ca2+ exchanger is key in Na+ import, and its inhibition prevents hypoxic adaptation, highlighting Na+'s essential role.