TY - JOUR
T1 - Age-related changes in axonal and mitochondrial ultrastructure and function in white matter
AU - Stahon, Katharine E.
AU - Bastian, Chinthasagar
AU - Griffith, Shelby
AU - Kidd, Grahame J.
AU - Brunet, Sylvain
AU - Baltan, Selva
N1 - Publisher Copyright:
© 2016 the authors.
PY - 2016/9/28
Y1 - 2016/9/28
N2 - 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.
AB - 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.
KW - Aging
KW - Axon
KW - Mitochondrial dynamic
KW - Myelin
KW - Neurodegeneration
KW - Three-dimensional electron microscopy
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U2 - 10.1523/JNEUROSCI.1316-16.2016
DO - 10.1523/JNEUROSCI.1316-16.2016
M3 - Article
C2 - 27683897
AN - SCOPUS:84989166283
SN - 0270-6474
VL - 36
SP - 9990
EP - 10001
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 39
ER -