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.
journal_name
Mol Biol Celljournal_title
Molecular biology of the cellauthors
Lowery J,Jain N,Kuczmarski ER,Mahammad S,Goldman A,Gelfand VI,Opal P,Goldman RDdoi
10.1091/mbc.E15-09-0627subject
Has Abstractpub_date
2016-02-15 00:00:00pages
608-16issue
4eissn
1059-1524issn
1939-4586pii
mbc.E15-09-0627journal_volume
27pub_type
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