Mitochondria Help Regulate Activation of Adult Neural Stem Cells

dentate gyrus nuerogenesis
Newly produced neurons (red) in the dentate gyrus with cell nuclei (blue) and a marker for immature neurons (green). Credit: Knobloch Lab – UNIL

Some adult brain regions have dormant neural stem cells that can be reactivated to form new neurons. But the transition from quiescence to proliferation is still poorly understood.

Now, a team led by researchers from the Universities of Geneva (UNIGE) and Lausanne (UNIL) has discovered the importance of cell metabolism in this process and identified how to wake up and reactivate these neural stem cells.

Biologists boosted the number of new neurons in the brains of adult and even elderly mice. The findings hold promise for the treatment of neurodegenerative diseases.

The Role of Neural Stem Cells

Stem cells can replicate themselves indefinitely and give rise to differentiated cells with more specialized functions. During embryonic development, neural stem cells (NSCs) build the brain, generating all central nervous system cells, including neurons.

Surprisingly, NSCs remain in specific brain regions even after the brain has fully formed and can generate new neurons throughout life. Adult neurogenesis is an important biological phenomenon for specific functions such as learning and memory processes.

In the adult brain, however, these stem cells become more silent or “dormant,” and their capacity for renewal and differentiation decreases. As a result, neurogenesis declines markedly with age.

Mitochondrial Pyruvate Transporter

The labs of Jean-Claude Martinou, Emeritus Professor in the Department of Molecular and Cellular Biology at the UNIGE Faculty of Science, and Marlen Knobloch, Associate Professor in the Department of Biomedical Sciences at the UNIL Faculty of Biology and Medicine, have found a way for adult neural stem cells to wake up from their dormant state and become active.

“We found that mitochondria, the energy-producing organelles within cells, are involved in regulating the level of activation of adult NSCs,”

said Francesco Petrelli, research fellow at UNIL and co-first author of the study with Valentina Scandella.

The mitochondrial pyruvate transporter (MPC), a protein complex discovered in Professor Martinou’s lab eleven years ago, is particularly important in this regulation. Its activity influences the metabolic options available to a cell.

Scientists can wake up dormant cells by modifying their mitochondrial metabolism if they understand the metabolic pathways that distinguish active cells from dormant cells.

Redirecting Metabolic Pathways

MPC activity has been inhibited by biologists using chemical inhibitors or by creating mutant mice for the Mpc1gene. The scientists were able to activate dormant NSCs and thus generate new neurons in the brains of adult and even aged mice using these pharmacological and genetic approaches.

“With this work, we show that redirection of metabolic pathways can directly influence the activity state of adult NSCs and consequently the number of new neurons generated,”

said co-lead author Professor Knobloch.

The results of the study shed light on the role of cell metabolism in neurogenesis regulation and could eventually lead to treatments for conditions like depression or neurodegenerative diseases.

  1. Francesco Petrelli et al. Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells. Science Advances (2023) Vol 9, Issue 9 DOI: 10.1126/sciadv.add5220