Structural basis of mitochondrial receptor binding and constriction by DRP1

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Mitochondrial dynamics, including fission, are crucial for cellular health.
• Dynamin-related protein 1 (DRP1) and its receptors (MID49, MID51, MFF) mediate mitochondrial fission.
• The precise mechanisms of DRP1 recruitment and regulation by its receptors remain unclear.

Purpose of the Study:

• To elucidate the structural mechanisms of DRP1 assembly and regulation by its mitochondrial receptors.
• To understand how nucleotide binding and hydrolysis control DRP1 function in mitochondrial fission.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structure of full-length human DRP1 co-assembled with MID49.
• Analysis of structure- and disease-based mutations in DRP1.

Main Results:

• GTP binding induces DRP1 elongation and rotation, facilitating polymerization into linear filaments with MID49 or MID51.
• GTP hydrolysis and exchange trigger MID receptor dissociation, filament shortening, and DRP1 ring formation.
• The study provides structural insights into nucleotide-driven allostery governing DRP1 function.

Conclusions:

• The findings reveal the dynamic conformational changes of DRP1 during mitochondrial fission.
• This work clarifies how DRP1 receptors recruit and regulate DRP1 polymerization and ring constriction.
• Understanding these mechanisms is key for comprehending mitochondrial inheritance, genome maintenance, and metabolic adaptation.