The tumor suppressor Parkin exerts anticancer effects through regulating mitochondrial GAPDH activity

Area of Science:

• Molecular Biology
• Oncology
• Cellular Metabolism

Background:

• Cancer cells rely heavily on glycolysis for energy, with GAPDH being a key enzyme.
• Parkin, a tumor suppressor, regulates mitophagy, but its cancer-fighting mechanisms are unclear.
• Understanding Parkin's role in cancer is crucial for developing new therapeutic strategies.

Purpose of the Study:

• To elucidate the tumor suppression mechanism of Parkin in human cervical cancer.
• To identify Parkin's substrates and understand its role in regulating cellular metabolism and mitophagy.

Main Methods:

• Identified mitochondrial GAPDH as a substrate of the E3 ubiquitin ligase Parkin.
• Investigated the role of PINK1 kinase in GAPDH mitochondrial translocation.
• Analyzed the effects of GAPDH ubiquitination on its activity, phosphorylation, and the glycolytic pathway.
• Studied the involvement of PHB2 in Parkin-mediated mitophagy.
• Conducted in vivo experiments to assess the impact of GAPDH mutation on tumorigenesis.

Main Results:

• Parkin ubiquitinates mitochondrial GAPDH at specific sites (K186, K215, K219), reducing its enzyme activity and inhibiting glycolysis.
• PINK1-driven mitochondrial translocation of GAPDH is essential for Parkin-mediated ubiquitination and subsequent mitophagy.
• GAPDH ubiquitination is required for mitophagy, which suppresses cervical cancer cell growth, indicating mitophagy as a cell death mechanism.
• PHB2 stabilizes PINK1, mediating GAPDH ubiquitination-induced mitophagy.
• GAPDH mutations accelerate tumorigenesis by increasing glycolysis in cervical cancer.

Conclusions:

• Parkin exerts its anticancer function by ubiquitinating mitochondrial GAPDH, thereby inhibiting glycolysis and promoting mitophagy.
• The Parkin-PINK1-GAPDH-PHB2 axis regulates energy metabolism and mitophagy, offering a novel therapeutic target for cervical cancer.
• This study provides a molecular basis for developing new drugs targeting Parkin's tumor-suppressive pathway in human cervical cancer.