Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex

By A. Misko, Sirui Jiang, I. Wegorzewska, J. Milbrandt, R. Baloh. Journal of Neuroscience, 2010

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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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/79dc63145f81c0fc08e1b3f23eacbf2727ff497f

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Citations in the corpus

Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration (2012, background): “Deleting Mfn2 or expressing mutant MFN2 in neurons resulted in longer pauses and slower anterograde and retrograde movement”
Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, positive): “…the sequestration and clearance of mitochondria by increasing mitochondrial ﬁssion, which precedes mitophagy (Twig et al , 2008; Tanaka et al , 2010) Milton (Misko et al , 2010), thus by decreasing Mfn1/2 and Miro1/2 protein levels parkin can affect both mitochondrial dynamics and transport.”
Mitochondria, oxidative stress and neurodegeneration. (2012, background): “MFN2 may also be involved in axonal transport of mitochondria by interaction with miro (Miro1/Miro2) and milton (OIP106/GRIF1) proteins, which link mitochondria to kinesin motors [30].”
Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. (2010, background): “Recently, MFN-2 has also been found to be necessary for the transport of mitochondria and interacts with the Miro/Milton complex (56).”
Lipids of mitochondria. (2013, background): “The OMM localized Mfn2 belongs to the family of dynamin-like GTPases and mediates mitochondrial fusion and interaction with Miro (mitochondrial rho GTPase)/Milton complex [289,290].”
Mechanisms of mesenchymal stem/stromal cell function (2016, background): “Mitofusin 1 and 2 may also regulate mitochondria transfer as they are known to interact with Miro-1 and Miro-2 as well as TREK1/ TREK2 in the adaptor–motor protein complex [132].”
Mitochondrial dynamics and mitochondrial quality control (2014, background): “Milton, and loss of Mfn2 alone is sufficient to cause a defect in mitochondrial transport in neurons [35].”