Cellular metabolism is essential for the behavior of adult neural stem/progenitor cells (NSPC). These cells can be reactivated to form new neurons. However, its role in the transition from quiescence to proliferation has yet to be fully understood.
A team led by scientists from the Universities of Geneva (UNIGE) and Lausanne (UNIL) has discovered the importance of cell metabolism in this process and identified how to awaken and reactivate these neural stem cells. They successfully increased the number of new neurons in the brains of adult and even older mice.
The brain is constructed during embryonic development by neural stem cells (NSCs), which produce all other cells of the central nervous system, including neurons. Interestingly, NSCs continue to grow and can produce new neurons in specific brain regions even after the brain has fully developed. Adult neurogenesis is a biological process critical to certain tasks, including memory and learning.
In the adult brain, however, these stem cells become quieter or “dormant” and reduce their ability to renew and differentiate. As a result, neurogenesis declines significantly with age.
Scientists have discovered a metabolic mechanism that allows adult NSCs to come out of their resting state and become active.
Francesco Petrelli, a research fellow at UNIL and co-first author of the study with Valentina Scandella, said: “We found that mitochondria, the energy-producing organelles in cells, regulate the activation level of mature NSCs.”
A crucial component in this control is played by the mitochondrial pyruvate transporter (MPC), a protein complex first identified eleven years ago by Professor Martinou’s team. Its activity affects the metabolic capabilities available to a cell. Scientists can wake up dormant cells by altering their mitochondrial metabolism by understanding the metabolic mechanisms that separate active cells from dormant ones.
By using chemical inhibitors or creating mutant mice for the Mpc1 gene, biologists have been able to block MPC activity. The scientists stimulated dormant NSCs and then generated new neurons in the brains of adult and even aged mice using pharmacological and genetic approaches.
Professor Knobloch, co-lead author of the study, said: “With this work, we show that redirection of metabolic pathways can directly influence the activity status of mature NSCs and, consequently, the number of new neurons generated.”
Jean-Claude Martinou, co-lead author of the study, said: “These results shed new light on the role of cell metabolism in regulating neurogenesis. In the long term, these results could lead to potential treatments for conditions such as depression or neurodegenerative diseases.”
- Francesco Petrelli, Valentina Scandella et al. Mitochondrial pyruvate metabolism regulates the activation of dormant adult neural stem cells. Science Advances, March 1, 2023, Vol 9, Number 9. DOI: 10.1126/sciadv.add5220