A new mitofusin topology places the redox-regulated C terminus in the mitochondrial intermembrane space

Sevan Mattie, Jan Riemer, Jeremy G. Wideman, Heidi M. McBride

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Mitochondrial fusion occurs in many eukaryotes, including animals, plants, and fungi. It is essential for cellular homeostasis, and yet the underlying mechanisms remain elusive. Comparative analyses and phylogenetic reconstructions revealed that fungal Fzo1 and animal Mitofusin proteins are highly diverged from one another and lack strong sequence similarity. Bioinformatic analysis showed that fungal Fzo1 proteins exhibit two predicted transmembrane domains, whereas metazoan Mitofusins contain only a single transmembrane domain. This prediction contradicts the current models, suggesting that both animal and fungal proteins share one topology. This newly predicted topology of Mfn1 and Mfn2 was demonstrated biochemically, confirming that the C-terminal, redox-sensitive cysteine residues reside within the intermembrane space (IMS). Functional experiments established that redox-mediated disulfide modifications within the IMS domain are key modulators of reversible Mfn oligomerization that drives fusion. Together, these results lead to a revised understanding of Mfns as single-spanning outer membrane proteins with an Nout-Cin orientation, providing functional insight into the IMS contribution to redox-regulated fusion events.

Original languageEnglish (US)
Pages (from-to)507-515
Number of pages9
JournalJournal of Cell Biology
Volume217
Issue number2
DOIs
StatePublished - Feb 1 2018

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'A new mitofusin topology places the redox-regulated C terminus in the mitochondrial intermembrane space'. Together they form a unique fingerprint.

Cite this