Bax-PGAM5L-Drp1 complex is required for intrinsic apoptosis execution

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• Intrinsic apoptosis eliminates cells with DNA damage or oncogene dysregulation.
• PGAM5, a phosphoglycerate mutase family member, has long (PGAM5L) and short (PGAM5S) splicing variants.
• PGAM5 is known to be involved in necrosis pathways, but its role in intrinsic apoptosis is debated.

Purpose of the Study:

• To investigate the role of PGAM5 variants in intrinsic apoptosis.
• To elucidate the molecular mechanism of PGAM5 in apoptosis execution.
• To evaluate the anti-cancer potential of arenobufagin in colorectal cancer (CRC) models.

Main Methods:

• Studied intrinsic apoptosis induced by arenobufagin and staurosporine.
• Utilized gene knockdown and transfection techniques in HCT116 cells (including Bax knockout).
• Investigated protein interactions and cellular localization using co-immunoprecipitation and microscopy.
• Assessed anti-cancer effects in orthotropic and heterotropic CRC models.

Main Results:

• PGAM5L, but not PGAM5S, is crucial for Bax activation and Drp1 dephosphorylation in intrinsic apoptosis.
• Knockdown of PGAM5L impedes Bax translocation to mitochondria and reduces mitochondrial fission.
• A Bax-PGAM5L-Drp1 complex is formed and is essential for apoptosis execution, observed in vitro and in vivo.
• Arenobufagin demonstrates significant anti-cancer effects in CRC models with lower toxicity than cisplatin.

Conclusions:

• The Bax-PGAM5L-Drp1 complex is a prerequisite for the execution of intrinsic apoptosis.
• PGAM5L plays a critical role in regulating mitochondrial dynamics during apoptosis.
• Arenobufagin is a promising anti-cancer agent for CRC, acting via the Bax-PGAM5L-Drp1 pathway.