Intracellular pH Modulates Autophagy and Mitophagy.

Area of Science:

• Cell Biology
• Neuroscience
• Mitochondrial Dynamics

Background:

• Mitophagy, the selective autophagic removal of mitochondria, is crucial for cellular quality control.
• Dysfunctional mitophagy is linked to neurodegenerative diseases like Parkinson's disease.
• Triggers for mitophagy are not fully understood, hindering therapeutic development.

Purpose of the Study:

• To investigate the role of cytosolic pH in regulating mitophagy.
• To determine if mitochondrial membrane potential or cytosolic pH is the primary trigger for mitophagy induction.

Main Methods:

• Utilized the mitochondrial uncoupler FCCP to induce mitophagy.
• Employed the ionophore nigericin to alter cytosolic pH.
• Used monensin to manipulate intracellular pH levels.
• Assessed mitophagy induction and its dependence on PINK1/PARKIN pathways.

Main Results:

• FCCP-induced mitophagy is independent of mitochondrial membrane potential but dependent on cytosolic acidification.
• Nigericin also induces mitophagy, correlating with reduced cytosolic pH.
• Elevating intracellular pH with monensin inhibits FCCP- and nigericin-induced mitophagy.
• Both PINK1/PARKIN-dependent and -independent mitophagy pathways are affected by pH changes.

Conclusions:

• Intracellular pH is a critical regulator of mitochondrial quality control via mitophagy.
• Cytosolic acidification, rather than changes in mitochondrial membrane potential, can trigger mitophagy.
• These findings offer new insights into the pathogenesis of neurodegenerative diseases and potential therapeutic targets.