Mitochondrial dysfunction underlies cognitive defects as a result of neural stem cell depletion and impaired neurogenesis

Mitochondrial dysfunction is a common feature of many genetic disorders that target the brain and cognition. However, the exact role these organelles play in the etiology of such disorders is not understood. Here, we show that mitochondrial dysfunction impairs brain development, depletes the adult n...

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Bibliographic Details
Published in:Human molecular genetics 2017-09, Vol.26 (17), p.3327-3341
Main Authors: Khacho, Mireille, Clark, Alysen, Svoboda, Devon S, MacLaurin, Jason G, Lagace, Diane C, Park, David S, Slack, Ruth S
Format: Article
Language:English
Subjects:
Animals
Apoptosis Inducing Factor - metabolism
Brain - metabolism
Cell Differentiation
Cell Proliferation
Cognition
Cognitive Dysfunction - metabolism
Humans
Mice
Mice, Transgenic
Mitochondria - metabolism
Mitochondria - physiology
Neural Stem Cells - metabolism
Neurodegenerative Diseases - metabolism
Neurogenesis - genetics
Neurogenesis - physiology
Neurons - metabolism
Signal Transduction
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Summary:Mitochondrial dysfunction is a common feature of many genetic disorders that target the brain and cognition. However, the exact role these organelles play in the etiology of such disorders is not understood. Here, we show that mitochondrial dysfunction impairs brain development, depletes the adult neural stem cell (NSC) pool and impacts embryonic and adult neurogenesis. Using deletion of the mitochondrial oxidoreductase AIF as a genetic model of mitochondrial and neurodegenerative diseases revealed the importance of mitochondria in multiple steps of the neurogenic process. Developmentally, impaired mitochondrial function causes defects in NSC self-renewal, neural progenitor cell proliferation and cell cycle exit, as well as neuronal differentiation. Sustained mitochondrial dysfunction into adulthood leads to NSC depletion, loss of adult neurogenesis and manifests as a decline in brain function and cognitive impairment. These data demonstrate that mitochondrial dysfunction, as observed in genetic mitochondrial and neurodegenerative diseases, underlies the decline of brain function and cognition due to impaired stem cell maintenance and neurogenesis.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddx217