Mitofusin 2 Is Necessary for Transport of Axonal Mitochondria and Interacts with the Miro/Milton Complex
TLDR
Evidence is presented that Mfn2 is directly involved in and required for axonal mitochondrial transport, distinct from its role in mitochondrial fusion, and important insight is offered into the cell type specificity and molecular mechanisms of axonal degeneration in CMT2A and dominant optic atrophy.Abstract:
Mitofusins (Mfn1 and Mfn2) are outer mitochondrial membrane proteins involved in regulating mitochondrial dynamics. Mutations in Mfn2 cause Charcot-Marie-Tooth disease (CMT) type 2A, an inherited disease characterized by degeneration of long peripheral axons, but the nature of this tissue selectivity remains unknown. Here, we present evidence that Mfn2 is directly involved in and required for axonal mitochondrial transport, distinct from its role in mitochondrial fusion. Live imaging of neurons cultured from Mfn2 knock-out mice or neurons expressing Mfn2 disease mutants shows that axonal mitochondria spend more time paused and undergo slower anterograde and retrograde movements, indicating an alteration in attachment to microtubule-based transport systems. Furthermore, Mfn2 disruption altered mitochondrial movement selectively, leaving transport of other organelles intact. Importantly, both Mfn1 and Mfn2 interact with mammalian Miro (Miro1/Miro2) and Milton (OIP106/GRIF1) proteins, members of the molecular complex that links mitochondria to kinesin motors. Knockdown of Miro2 in cultured neurons produced transport deficits identical to loss of Mfn2, indicating that both proteins must be present at the outer membrane to mediate axonal mitochondrial transport. In contrast, disruption of mitochondrial fusion via knockdown of the inner mitochondrial membrane protein Opa1 had no effect on mitochondrial motility, indicating that loss of fusion does not inherently alter mitochondrial transport. These experiments identify a role for mitofusins in directly regulating mitochondrial transport and offer important insight into the cell type specificity and molecular mechanisms of axonal degeneration in CMT2A and dominant optic atrophy.read more
Citations
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References
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Journal ArticleDOI
Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development
TL;DR: It is concluded that Mfn1 and Mfn2 have both redundant and distinct functions and act in three separate molecular complexes to promote mitochondrial fusion, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population.
Journal ArticleDOI
Mitofusin 2 tethers endoplasmic reticulum to mitochondria
TL;DR: It is shown that mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot–Marie–Tooth type IIa, is enriched at the ER–mitochondria interface, and that it tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca2+ uptake.
Journal ArticleDOI
Mitochondria: Dynamic Organelles in Disease, Aging, and Development
TL;DR: Recent work is discussed that suggests that the dynamics (fusion and fission) of these organelles is important in development and disease.
Journal ArticleDOI
Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.
Stephan Züchner,Stephan Züchner,Irina V. Mersiyanova,Maria Muglia,Nisrine Bissar-Tadmouri,Nisrine Bissar-Tadmouri,Julie M. Rochelle,Elena L. Dadali,Mario Zappia,Eva Nelis,Alessandra Patitucci,Jan Senderek,Yesim Parman,Oleg V. Evgrafov,Peter De Jonghe,Yuji Takahashi,Shoij Tsuji,Margaret A. Pericak-Vance,Aldo Quattrone,Esra Battologlu,Alexander V. Polyakov,Vincent Timmerman,J. Michael Schröder,Jeffery M. Vance +23 more
TL;DR: It is concluded that the primary gene mutated in CMT2A is MFN2, and seven large pedigrees affected with Charcot-Marie-Tooth neuropathy type 2A are concluded.
Journal ArticleDOI
Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.
Cécile Delettre,Guy Lenaers,Jean-Michel Griffoin,Nadine Gigarel,Corinne Lorenzo,Pascale Belenguer,Laetitia Pelloquin,J. Grosgeorge,Claude Turc-Carel,Eric Perret,Catherine Astarie-Dequeker,Laetitia Lasquellec,B. Arnaud,Bernard Ducommun,Josseline Kaplan,Christian P. Hamel +15 more
TL;DR: A nuclear gene, OPA1, is described here a nuclear gene that maps within the candidate region and encodes a dynamin-related protein localized to mitochondria, demonstrating a role for mitochondria in retinal ganglion cell pathophysiology.
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