Mfn2-dependent fusion pathway of PE-enriched micron-sized vesicles.

Autor:	Peñalva DA; Instituto de Investigaciones Bioquímicas de Bahía Blanca, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional del Sur, Bahía Blanca B8000, Argentina.; Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca B8000, Argentina., Monnappa AK; Instituto de Investigación Biomédica Hospital Doce de Octubre (imas12), Madrid 28041, Spain., Natale P; Instituto de Investigación Biomédica Hospital Doce de Octubre (imas12), Madrid 28041, Spain.; Departamento Química Física, Universidad Complutense de Madrid, Madrid 28041, Spain.; Instituto Pluridisciplinar, Universidad Complutense de Madrid, Madrid 28041, Spain., López-Montero I; Instituto de Investigación Biomédica Hospital Doce de Octubre (imas12), Madrid 28041, Spain.; Departamento Química Física, Universidad Complutense de Madrid, Madrid 28041, Spain.; Instituto Pluridisciplinar, Universidad Complutense de Madrid, Madrid 28041, Spain.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jul 23; Vol. 121 (30), pp. e2313609121. Date of Electronic Publication: 2024 Jul 16.
DOI:	10.1073/pnas.2313609121
Abstrakt:	Mitofusins (Mfn1 and Mfn2) are the mitochondrial outer-membrane fusion proteins in mammals and belong to the dynamin superfamily of multidomain GTPases. Recent structural studies of truncated variants lacking alpha helical transmembrane domains suggested that Mfns dimerize to promote the approximation and the fusion of the mitochondrial outer membranes upon the hydrolysis of guanine 5'-triphosphate disodium salt (GTP). However, next to the presence of GTP, the fusion activity seems to require multiple regulatory factors that control the dynamics and kinetics of mitochondrial fusion through the formation of Mfn1-Mfn2 heterodimers. Here, we purified and reconstituted the full-length murine Mfn2 protein into giant unilamellar vesicles (GUVs) with different lipid compositions. The incubation with GTP resulted in the fusion of Mfn2-GUVs. High-speed video-microscopy showed that the Mfn2-dependent membrane fusion pathway progressed through a zipper mechanism where the formation and growth of an adhesion patch eventually led to the formation of a membrane opening at the rim of the septum. The presence of physiological concentration (up to 30 mol%) of dioleoyl-phosphatidylethanolamine (DOPE) was shown to be a requisite to observe GTP-induced Mfn2-dependent fusion. Our observations show that Mfn2 alone can promote the fusion of micron-sized DOPE-enriched vesicles without the requirement of regulatory cofactors, such as membrane curvature, or the assistance of other proteins. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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