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.
Original language | English (US) |
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Pages (from-to) | 608-616 |
Number of pages | 9 |
Journal | Molecular biology of the cell |
Volume | 27 |
Issue number | 4 |
DOIs | |
State | Published - Feb 15 2016 |
Funding
We acknowledge the assistance of Kyung Hee Myung in the preparation of cells for light and electron microscopy and Wen Lu for help with the statistical analysis of mitochondrial fluorescence. The Goldman Laboratory is funded by grants from Hannah''s Hope Fund and National Institute of General Medical Sciences Grant PO1GM096971. The Opal Laboratory received funding from Hannah''s Hope Fund and is funded by the National Institute of Neurological Disorders and Stroke (National Institutes of Health Grants R01NS062051 and R01NS082351). The Gelfand Laboratory is supported by National Institute of General Medical Sciences Grants PO1 GM096971 and R01 GM052111.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology