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Articles, Neurobiology of Disease

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 and Selva Baltan
Journal of Neuroscience 28 September 2016, 36 (39) 9990-10001; DOI: https://doi.org/10.1523/JNEUROSCI.1316-16.2016
Katharine E. Stahon
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Chinthasagar Bastian
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Shelby Griffith
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Grahame J. Kidd
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Sylvain Brunet
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Selva Baltan
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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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.

SIGNIFICANCE STATEMENT Aging is a common risk factor for a number of neurodegenerative diseases, including stroke. Mitochondrial dysfunction and oxidative damage with age are hypothesized to increase risk for stroke. We compared axon–myelin–node–mitochondrion–smooth endoplasmic reticulum (SER) interactions in white matter obtained at 1 and 12 months. We show that aging axons have enlarged volume, thicker myelin, and elongated and thicker mitochondria. Furthermore, there are reduced SER connections to mitochondria that correlate with lower calnexin and calreticulin levels. Despite a prominent decrease in number, elongated aging mitochondria produce excessive stress markers with reduced ATP production. Because axons maintain function under these conditions, our study suggests that it is important to understand the process of normal brain aging to identify neurodegenerative changes.

  • aging
  • axon
  • mitochondrial dynamic
  • myelin
  • neurodegeneration
  • three-dimensional electron microscopy
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The Journal of Neuroscience: 36 (39)
Journal of Neuroscience
Vol. 36, Issue 39
28 Sep 2016
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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
Journal of Neuroscience 28 September 2016, 36 (39) 9990-10001; DOI: 10.1523/JNEUROSCI.1316-16.2016

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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
Journal of Neuroscience 28 September 2016, 36 (39) 9990-10001; DOI: 10.1523/JNEUROSCI.1316-16.2016
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Keywords

  • aging
  • axon
  • mitochondrial dynamic
  • myelin
  • neurodegeneration
  • three-dimensional electron microscopy

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