Mitofusin2 Mutations Disrupt Axonal Mitochondrial Positioning and Promote Axon Degeneration

Abstract

Summary Alterations in mitochondrial dynamics (fission, fusion and movement) are implicated in many neurodegenerative diseases, from rare genetic disorders such as Charcot-Marie-Tooth disease, to common conditions including Alzheimer’s disease. However, the relationship between altered mitochondrial dynamics and neurodegeneration is incompletely understood. Here we show that disease associated MFN2 proteins suppressed both mitochondrial fusion and transport, and produced classic features of segmental axonal degeneration without cell body death, including neurofilament filled swellings, loss of calcium homeostasis, and accumulation of reactive oxygen species. By contrast, depletion of Opa1 suppressed mitochondrial fusion while sparing transport, and did not induce axonal degeneration. Axon degeneration induced by mutant MFN2 proteins correlated with the disruption of the proper mitochondrial positioning within axons, rather than loss of overall mitochondrial movement, or global mitochondrial dysfunction. We also found that augmenting expression of MFN1 rescued the axonal degeneration caused by MFN2 mutants, suggesting a possible therapeutic strategy for Charcot-Marie-Tooth disease. These experiments provide evidence that the ability of mitochondria to sense energy requirements and localize properly within axons is key to maintaining axonal integrity, and may be a common pathway by which disruptions in axonal transport contribute to neurodegeneration.

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

“…Mitochondrial network dynamics plays a major role in mitochondria quality control and has emerged as a central actor in neurodegeneration [45][46][47] . Generally, the mitochondrial network becomes fragmented in response to stress, in order to facilitate mitophagy of damaged mitochondria, whereas a filamentous network ensures a better response to oxidative stress, both through dilution of stress molecules and compensatory mechanisms 48,49 .…”

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

“…In syntaphilin-null unmyelinated axons in vitro, mitochondrial stationary site volume is decreased and the number of motile mitochondria is increased (24). Overexpression of syntaphilin increased axonal stationary site size and reduced the number of motile mitochondria (25). The purpose of the present study is twofold.…”

Mitochondrial dynamics in neuronal injury, development and plasticity

“…However, other groups have challenged this model, suggesting instead that deletion of Mfn2 increases ER-mitochondrial association and, in turn, are questioning whether Mfn2, indeed, localizes to the ER (Filadi et al, 2015;Cosson et al, 2012). Regardless of the role Mfn2 has in ER-mitochondrial contacts, the importance of mitochondrial fusion proteins -particularly in neuronal cells -is highlighted by the fact that hypomorphic mutations in Mfn2 are most often responsible for autosomal dominant Charcot-Marie-Tooth (CMT) disease, axonal, type 2A2 (CMT2A2) (Chapman et al, 2013;Misko et al, 2012;Niemann et al, 2014;Yu-Wai-Man et al, 2011), a common peripheral neuropathy (Züchner et al, 2004), whereas mutations in Opa1 are the most common cause of hereditary blindness, i.e. autosomal dominant optic atrophy (ADOA) (Yu-Wai-Man et al, 2011;Alexander et al, 2000;Zanna et al, 2008).…”

“…The size of mitochondria as determined by the equilibrium between fission and fusion influences mitochondrial transport to a significant degree, with either extreme mitochondrial fission or fusion capable of stalling mitochondrial transport in neurons (Zanna et al, 2008;Misko et al, 2012;Chapman et al, 2013;Baloh, 2008;Barbosa et al, 2014;DuBoff et al, 2013;Sheng, 2014). Neurons are especially sensitive to perturbations in mitochondrial transport given the length and complexity of their axons and dendrites.…”