title: Abnormal intermediate filament organization alters mitochondrial motility in giant axonal neuropathy fibroblasts.
abstract: Giant axonal neuropathy (GAN) is a rare disease caused by mutations in the GAN gene, which encodes gigaxonin, an E3 ligase adapter that targets intermediate filament (IF) proteins for degradation in numerous cell types, including neurons and fibroblasts. The cellular hallmark of GAN pathology is the formation of large aggregates and bundles of IFs. In this study, we show that both the distribution and motility of mitochondria are altered in GAN fibroblasts and this is attributable to their association with vimentin IF aggregates and bundles. Transient expression of wild-type gigaxonin in GAN fibroblasts reduces the number of IF aggregates and bundles, restoring mitochondrial motility. Conversely, silencing the expression of gigaxonin in control fibroblasts leads to changes in IF organization similar to that of GAN patient fibroblasts and a coincident loss of mitochondrial motility. The inhibition of mitochondrial motility in GAN fibroblasts is not due to a global inhibition of organelle translocation, as lysosome motility is normal. Our findings demonstrate that it is the pathological changes in IF organization that cause the loss of mitochondrial motility.
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611.
authors.forename: Jason
authors.initials: J
authors.lastname: Lowery
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611 Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Jain
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Kuczmarski
authors.affiliation: Stem Cell and Cancer Research Institute, Michael DeGroote Centre for Learning and Discovery, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Saleemulla
authors.initials: S
authors.lastname: Mahammad
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611.
authors.forename: Anne
authors.initials: A
authors.lastname: Goldman
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Gelfand
authors.affiliation: Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Puneet
authors.initials: P
authors.lastname: Opal
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611 r-goldman@northwestern.edu.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Goldman
mesh_terms: D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D056768:Giant Axonal Neuropathy / Q000503:physiopathology*; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D009154:Mutation; D061251:Primary Cell Culture; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; C416508:GAN protein, human; D034741:RNA, Small Interfering; D014746:Vimentin