Abnormal intermediate filament organization alters mitochondrial motility in giant axonal neuropathy fibroblasts

Jason Lowery, Nikhil Jain, Edward R. Kuczmarski, Saleemulla Mahammad, Anne Goldman, Vladimir I. Gelfand, Puneet Opal, Robert D. Goldman*

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Scopus citations

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 languageEnglish (US)
Pages (from-to)608-616
Number of pages9
JournalMolecular biology of the cell
Volume27
Issue number4
DOIs
StatePublished - Feb 15 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Abnormal intermediate filament organization alters mitochondrial motility in giant axonal neuropathy fibroblasts'. Together they form a unique fingerprint.

  • Cite this