TY - JOUR
T1 - Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration
AU - Misko, Albert L.
AU - Sasaki, Yo
AU - Tuck, Elizabeth
AU - Milbrandt, Jeffrey
AU - Baloh, Robert H.
PY - 2012/3/21
Y1 - 2012/3/21
N2 - Alterations in mitochondrial dynamics (fission, fusion, and movement) are implicated in many neurodegenerative diseases, from rare genetic disorders suchasCharcot-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 didnotinduceaxonaldegeneration.AxondegenerationinducedbymutantMFN2proteinscorrelatedwith thedisruptionofthepropermitochondrial 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.
AB - Alterations in mitochondrial dynamics (fission, fusion, and movement) are implicated in many neurodegenerative diseases, from rare genetic disorders suchasCharcot-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 didnotinduceaxonaldegeneration.AxondegenerationinducedbymutantMFN2proteinscorrelatedwith thedisruptionofthepropermitochondrial 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.
UR - http://www.scopus.com/inward/record.url?scp=84858397292&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.6338-11.2012
DO - 10.1523/JNEUROSCI.6338-11.2012
M3 - Article
C2 - 22442078
AN - SCOPUS:84858397292
SN - 0270-6474
VL - 32
SP - 4145
EP - 4155
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 12
ER -