PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.

Area of Science:

• Mitochondrial biology and cellular dynamics.
• Protein regulation and post-translational modifications.

Background:

• Mitochondrial dynamics are governed by dynamin GTPases like mitofusin 1 (MFN1), mitofusin 2 (MFN2), and dynamin-related protein 1 (DRP1).
• Phosphoglycerate mutase 5 (PGAM5) influences MFN2 and DRP1 phosphorylation and function, but its regulatory mechanisms remain unclear.

Purpose of the Study:

• To elucidate the precise regulation of phosphoglycerate mutase 5 (PGAM5) activity.
• To investigate the role of PGAM5 oligomerization and localization in controlling mitochondrial dynamics.

Main Methods:

• Analysis of PGAM5 oligomerization states (dodecamer vs. dimer) under cellular stress conditions.
• Assessment of PGAM5's differential binding affinity to MFN2 and DRP1.
• Investigation of PGAM5 cleavage by inner mitochondrial proteases PARL and OMA1.
• Tracking of PGAM5 relocalization to the cytosol post-cleavage.

Main Results:

• Under depolarization and metabolic stress, PGAM5 shifts from dodecamers to dimers.
• PGAM5 dimers exhibit altered affinities for MFN2 and DRP1 compared to dodecamers.
• PGAM5 undergoes cleavage by PARL and OMA1, with a portion translocating to the cytosol.

Conclusions:

• PGAM5 oligomerization state (dodecamer vs. dimer) is a key regulator of its function.
• Cleavage-induced relocalization of PGAM5 to the cytosol further modulates its activity.
• These regulatory events are critical for controlling mitochondrial dynamics during cellular stress.