A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Mitophagy is crucial for mitochondrial quality control, removing damaged mitochondria.
• Receptor-mediated mitophagy involves interactions between LC3 and mitophagy receptors like FUNDC1.
• The sensing mechanisms linking mitochondrial stress to mitophagy activation are not fully understood.

Purpose of the Study:

• To elucidate the signaling pathway that activates receptor-mediated mitophagy.
• To identify the molecular players involved in sensing mitochondrial damage and initiating mitophagy.

Main Methods:

• Investigated the interaction between PGAM5 phosphatase and the mitophagy receptor FUNDC1.
• Utilized biochemical assays to assess dephosphorylation of FUNDC1 at Serine-13.
• Employed knockdown and peptide inhibition strategies to study the role of PGAM5 and FUNDC1 phosphorylation in mitophagy.
• Examined the effect of CK2 phosphorylation on FUNDC1 activity.

Main Results:

• PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at Ser-13 upon mitochondrial stress (hypoxia, FCCP).
• Dephosphorylation of FUNDC1 by PGAM5 enhances its interaction with LC3, promoting mitophagy.
• PGAM5 knockdown or inhibition of FUNDC1 dephosphorylation abrogates mitophagy.
• CK2 phosphorylates FUNDC1, reversing the mitophagy-inducing effect of PGAM5.

Conclusions:

• A novel signaling pathway is identified, linking mitochondrial damage to FUNDC1 dephosphorylation by PGAM5.
• This dephosphorylation event is critical for initiating mitophagy by enhancing FUNDC1-LC3 interaction.
• The balance between PGAM5-mediated dephosphorylation and CK2-mediated phosphorylation of FUNDC1 regulates mitophagy activation.