Mitochondria as central regulators of neural stem cell fate and cognitive function

Abstract

Emerging evidence now indicates that mitochondria are central regulators of neural stem cell (NSC) fate decisions and are crucial for both neurodevelopment and adult neurogenesis, which in turn contribute to cognitive processes in the mature brain. Inherited mutations and accumulated damage to mitochondria over the course of ageing serve as key factors underlying cognitive defects in neurodevelopmental disorders and neurodegenerative diseases, respectively. In this Review, we explore the recent findings that implicate mitochondria as crucial regulators of NSC function and cognition. In this respect, mitochondria may serve as targets for stem-cell-based therapies and interventions for cognitive defects.

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Fig. 1: Mitochondrial metabolism and downstream metabolite signalling in stem cells.
Fig. 2: Mitochondrial structure and function during neurogenesis.
Fig. 3: Genetic versus non-genetic influence of mitochondrial dysfunction on NSC maintenance, neurogenesis and cognitive function.
Fig. 4: Potential therapies targeting mitochondria that would enhance adult neurogenesis and cognitive function.

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Acknowledgements

The authors thank D. Lagace, D. Patten and B. Fong for critical review of the manuscript. M.K. was supported by postdoctoral fellowships from the Heart and Stroke Foundation of Canada (HSFC), the Canadian Partnership for Stroke Recovery and the Brain Canada/Krembil Foundation. R.H. is supported by a postdoctoral fellowship from the Parkinson’s Research Consortium. This research was supported by grants from the Canadian Institutes of Health Research, the Brain Canada/Krembil Foundation and the HSFC to R.S.S.

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Nature Reviews Neuroscience thanks A. Prigione, M. Boldrini and N. Chandel for their contribution to the peer review of this work.

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R.S.S., M.K. and R.H. researched data for the article and made substantial contributions to the discussion of content and the review and editing of the manuscript before submission. M.K. and R.H. wrote the article.

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Correspondence to Ruth S. Slack.

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Glossary

Tricarboxylic acid (TCA) cycle

A series of metabolic reactions within the mitochondrial matrix that convert reduced carbon molecules to reducing equivalents that can donate electrons to the electron transport chain.

Electron transport chain

(ETC). A series of protein complexes that accept electrons from reducing equivalents in order to pump hydrogen ions into the intermembrane space of the mitochondria for establishment of an electrochemical gradient used to generate ATP.

Optic atrophy

Degeneration of the optic nerve that can be caused by mutations in the OPA1 gene that promote mitochondrial inner membrane fusion.

Oxidative phosphorylation

(OXPHOS). The process by which electrons are donated to the electron transport chain in the mitochondria to establish an electrochemical gradient and generate ATP with oxygen as a final electron acceptor.

Jumonji C domain

A protein motif that has histone demethylase catalytic activity.

Acetylation marks

Post-translational modifications consisting of acetyl groups that are used as a reversible regulatory mechanism for modifying protein function.

Mitochondrial respiration

The process by which mitochondria use reduced carbon molecules and oxygen to generate energy in the form of ATP.

Wolfram syndrome

(WS). A rare genetic disease primarily caused by mutations to the WFS1 gene that regulates calcium balance in cells; WS results in diabetes, optic atrophy and deafness in children.

Leigh syndrome

A rare genetic disease primarily caused by mutations affecting oxidative phosphorylation; Leigh syndrome results in developmental delay, cognitive impairment and motor decline.

COX deficiency

A genetic disease caused by mutations in cytochrome c oxidase (COX), a complex of the electron transport chain, resulting in encephalomyopathy, muscle atrophy and Leigh syndrome.

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Khacho, M., Harris, R. & Slack, R.S. Mitochondria as central regulators of neural stem cell fate and cognitive function. Nat Rev Neurosci 20, 34–48 (2019). https://doi.org/10.1038/s41583-018-0091-3

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