Age-related changes in axonal and mitochondrial ultrastructure and function in white matter

Katharine E. Stahon, Chinthasagar Bastian, Shelby Griffith, Grahame J. Kidd, Sylvain Brunet, Selva Baltan

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

The impact of aging on CNS white matter (WM) is of general interest because the global effects of aging on myelinated nerve fibers are more complex and profound than those in cortical gray matter. It is important to distinguish between axonal changes created by normal aging and those caused by neurodegenerative diseases, including multiple sclerosis, stroke, glaucoma, Alzheimer’s disease, and traumatic brain injury. Using three-dimensional electron microscopy, we show that in mouse optic nerve, which is a pure and fully myelinated WM tract, aging axons are larger, have thicker myelin, and are characterized by longer and thicker mitochondria, which are associated with altered levels of mitochondrial shaping proteins. These structural alterations in aging mitochondria correlate with lower ATP levels and increased generation of nitric oxide, protein nitration, and lipid peroxidation. Moreover, mitochondria-smooth endoplasmic reticulum interactions are compromised due to decreased associations and decreased levels of calnexin and calreticulin, suggesting a disruption in Ca2+ homeostasis and defective unfolded protein responses in aging axons. Despite these age-related modifications, axon function is sustained in aging WM, which suggests that age-dependent changes do not lead to irreversible functional decline under normal conditions, as is observed in neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)9990-10001
Number of pages12
JournalJournal of Neuroscience
Volume36
Issue number39
DOIs
StatePublished - Sep 28 2016
Externally publishedYes

Keywords

  • Aging
  • Axon
  • Mitochondrial dynamic
  • Myelin
  • Neurodegeneration
  • Three-dimensional electron microscopy

ASJC Scopus subject areas

  • Neuroscience(all)

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