Many people have heard the phrase “mitochondria are the powerhouse of the cell”, whether as a part of their biology studies at school, or from the various memes on social media. This is said because mitochondria are structures within cells that provide over 90% of the energy needed by the body. These tiny organelles are thought to have emerged over a billion years ago, when all organisms were single cells. The single-celled precursor to multicellular organisms engulfed another smaller single cell and hijacked its energy-producing mechanisms for its own use, and this engulfed cell eventually became the mitochondrion. This energy production more efficiently converts sugars into ATP, which provides energy in a form that the cell can use for its normal function.
However, only about 3% of the genes necessary for mitochondrial function are required to produce ATP, suggesting that these tiny structures may have many other roles. One of these was investigated in an exciting new study published in August in the journal Science. Researchers at the Université Libre de Bruxelles and Katholieke Universiteit Leuven have been studying the link between mitochondria and the development of the brain, a highly energy-intensive process.
Small differences in the rate and duration of neurogenesis between species are thought to be the origin of differences in brain size and complexity, and, ultimately, our ability to learn.
Brain development involves the multiplication of neural stem cells. These stem cells can either remain in an immature state and self-renew to form more stem cells, or they can change their “cellular fate” and differentiate into a more mature cell type, such as the nerve cells found in adult brains. This latter process is known as neurogenesis and is tightly regulated. Small differences in the rate and duration of neurogenesis between species are thought to be the origin of differences in brain size and complexity, and, ultimately, our ability to learn, although some studies have found that this association may be correlative rather than causative.
Mitochondria have previously been found to be highly dynamic. They can combine with other mitochondria (fusion) or they can split up (fission), and this has been associated with various types of stem cell fate changes. The novel finding of this study is that mitochondrial fission and fusion can also occur in neural stem cells during neurogenesis specifically. The future cell type of a stem cell is determined by whether the mitochondria in that cell undergo fusion or fission.
In the cells destined to self-renew, the mitochondria will fuse, whilst the cells that become nerve cells will show high levels of mitochondrial fission. In addition, treatment of the stem cells with drugs that increase mitochondrial fission promotes a nerve cell fate, whilst compounds that promoted fusion increased the proportion of cells that remained as immature stem cells. Interestingly, these results were found in both human and mouse cells grown in a petri dish, as well as in samples from mouse brains.
A better understanding of the role of mitochondria in healthy individuals will aid in the development of treatments for debilitating mitochondrial disorders.
However, this influence of mitochondrial dynamics has its limits. In mouse samples, mitochondria dynamics will only affect stem cell fate for 3 hours after the stem cell divides. Surprisingly, the authors found that in human samples this window was doubled to 6 hours. The author Vanderhaeghen speculates that “since this period of plasticity is much longer in human cells compared to mouse cells, it is tempting to speculate that it contributes to the increased self-renewal capacity of human progenitor cells, and thus to the uniquely developed brain and cognitive abilities of our species”. However, it is also important to note that human development occurs across an overall much longer timescale than mice, and this may also impact the development of our brains.
This finding has major implications in the field of cell reprogramming; the process of reverting mature cells to an immature state, with the potential to then develop these into a different type of mature cell. This has a theoretical clinical benefit. For example, a small skin cell sample could be taken, reverted to stem cells, and then to brain cells, which could then be transplanted to areas of the brain that are damaged in neurodegenerative disorders such as Alzheimer’s disease. Therefore, better understanding of how stem cells convert between cell types under normal conditions will enable scientists to better replicate these conditions in the laboratory.
Another implication of this work is its relevance to the study of mitochondrial diseases. These are rare disorders caused by mitochondrial failure, usually due to mutations in the genes vital for mitochondria function. Multiple organ systems are affected, particularly areas that require the greatest amounts of energy, such as the heart and other muscles, the brain, and the lungs., This can result in symptoms ranging from seizures, to strokes, to an inability to walk and developmental delays. Therefore, a better understanding of the role of mitochondria in healthy individuals will aid in the development of treatments for debilitating mitochondrial disorders.
Written by Susanna Riley and edited by Ailie McWhinnie.
Susanna’s thoughts… Despite many decades of work investigating the development and function of our brain, this area is still largely unknown and research is hindered by a range of factors, including but not limited to the challenge of accessing the brain for study, and the lack of effective and translatable model systems to investigate whole organ function. Therefore, any work that elucidates the role of well characterised organelles such as mitochondria and shows parallels between rodent and human models is much welcomed. However, the study of isolated cells in a petri dish (such as that performed in this article) is likely far removed from the complex web of interactions within a brain, during both development and adulthood, and so any results should be treated with caution before any conclusions about treatments can be definitively drawn.