A special latch in yeast mitofusin guarantees mitochondrial fusion by stabilizing self-assembly

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Mitochondria are dynamic organelles crucial for cellular health, undergoing fusion and fission.
• Outer mitochondrial membrane (OMM) fusion is mediated by mitofusins, GTPases essential for this process.
• Yeast utilizes a single mitofusin (Fzo1), unlike most eukaryotes with two, raising questions about its unique fusion mechanism.

Purpose of the Study:

• To elucidate the mechanism by which yeast Fzo1 solely catalyzes OMM fusion.
• To investigate the structural and functional roles of Fzo1, particularly its unique features compared to mammalian mitofusins.
• To understand how Fzo1 ensures efficient mitochondrial fusion with limited GTP consumption.

Main Methods:

• X-ray crystallography of truncated Fzo1 (Fzo1IM) in various nucleotide-bound states.
• Systematic functional studies to analyze Fzo1's mechanism and the role of its unique structural features.
• Analysis of Fzo1's interaction with the ubiquitin-proteasome system in relation to mitochondrial fusion.

Main Results:

• Fzo1 possesses an essential latch bulge (LB) domain, absent in mammalian mitofusins, critical for yeast viability.
• GTP-bound Fzo1IM dimerizes and adopts a closed conformation, which is stabilized by LB-mediated trans interactions even after GTP hydrolysis.
• This unique mechanism allows Fzo1 to remain dimerized in a closed state, potentially explaining its efficient function and regulation.

Conclusions:

• Yeast Fzo1 employs a novel mechanism involving a latch bulge for stable dimerization and efficient OMM fusion.
• This mechanism conserves GTP and provides insights into how a single mitofusin can effectively drive mitochondrial fusion.
• The findings broaden the understanding of mitochondrial dynamics and regulation in eukaryotes.