Age-Related Changes in Axonal and Mitochondrial Ultrastructure and Function in White Matter

Area of Science:

• Neuroscience
• Cell Biology
• Aging Research

Background:

• Aging profoundly impacts central nervous system (CNS) white matter (WM) structure and function.
• Distinguishing normal aging from neurodegenerative diseases like Alzheimer's and stroke is crucial.
• Mitochondrial dysfunction and oxidative stress are implicated in age-related neurodegeneration.

Purpose of the Study:

• To investigate the structural and functional changes in aging axons and their associated mitochondria.
• To compare age-related modifications in white matter with those seen in neurodegenerative conditions.
• To elucidate the role of mitochondria-smooth endoplasmic reticulum (SER) interactions in aging axons.

Main Methods:

• Utilized three-dimensional electron microscopy to examine mouse optic nerve structure.
• Compared white matter components (axon, myelin, mitochondria, SER) from young (1 month) and aged (12 months) mice.
• Assessed mitochondrial morphology, ATP levels, oxidative stress markers, and mitochondria-SER interactions.

Main Results:

• Aging axons exhibited increased volume, thicker myelin sheaths, and elongated, thicker mitochondria.
• Mitochondria showed altered shaping protein levels, reduced ATP production, and increased oxidative stress markers (nitric oxide, lipid peroxidation).
• Mitochondria-SER interactions were compromised, with decreased associations and lower calnexin/calreticulin levels, suggesting impaired calcium homeostasis and unfolded protein response.

Conclusions:

• Aging induces significant structural modifications in white matter axons and mitochondria.
• Despite age-related mitochondrial dysfunction and oxidative stress, axon function remains preserved in normal aging.
• Understanding normal aging processes is vital for identifying pathological changes in neurodegenerative diseases.