Abnormal Intermediate Filament Organization Alters Mitochondrial Motility in Giant Axonal Neuropathy Fibroblasts
| Autor: | Robert D. Goldman, Puneet Opal, Vladimir I. Gelfand, Saleemulla Mahammad, Anne E. Goldman, Nikhil Jain, Edward R. Kuczmarski, Jason Lowery |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Primary Cell Culture Intermediate Filaments Motility Vimentin Mitochondrion Microtubules Mitochondrial Dynamics Cell Line 03 medical and health sciences 0302 clinical medicine medicine Humans RNA Small Interfering Intermediate filament Molecular Biology Giant axonal neuropathy biology Articles Cell Biology Fibroblasts medicine.disease Mitochondria 3. Good health Cell biology Cytoskeletal Proteins 030104 developmental biology Intermediate filament organization Giant Axonal Neuropathy Cell Biology of Disease Mutation biology.protein RNA Interference Lysosomes 030217 neurology & neurosurgery |
| Zdroj: | Molecular Biology of the Cell, 27 (4) Molecular Biology of the Cell |
| ISSN: | 1939-4586 1059-1524 |
| Popis: | 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. Molecular Biology of the Cell, 27 (4) ISSN:1939-4586 ISSN:1059-1524 |
| Databáze: | OpenAIRE |
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