Organelles called mitochondria are asymmetrically apportioned to the daughters of dividing stem cells according to mitochondrial age. This finding sheds light on the mechanisms underlying asymmetric stem-cell division.
The thought of reversing the ageing process has tickled the human imagination for centuries. Despite the air of mystery surrounding the topic, rejuvenation occurs so naturally that we pay no attention to it — that is, when mothers give birth to offspring. Although babies originate from the germ cells of a mother and father who might be decades old, they do not inherit their parents' accumulated cellular damage, but get a fresh start. Writing in Science, Katajisto et al.1 suggest that such rejuvenation may also be a characteristic of the stem cells responsible for tissue maintenance.
Stem cells have some distinctive characteristics. They are long-lived, or even immortal, and can divide asymmetrically2. The difference between the daughter cells of an asymmetric stem-cell division is not subtle. One daughter inherits the mother's immortality and ability to give rise to many cell types. The other must leave the cosy stem-cell home, become mortal and commit to differentiating into a cell with a specialized identity, for example a cell of the gut wall, eschewing its broad potential in favour of excelling at one particular task.
Katajisto et al.1 focused on the stem cells of human mammary tissue. Samples taken from the tissue and cultured in vitro contain small, round, stem-cell-like cells and flat epithelial cells, which line the mammary ducts in vivo. The different daughters of mammary stem-cell divisions are therefore easily distinguished by microscopy, and their fates can be followed in vitro. To investigate whether asymmetric stem-cell division involves asymmetric apportioning of organelles to the two daughters, the authors developed assays that enabled them to tag organelles and then activate the tags at exact times. In this way, they could identify the organelles that were newly synthesized and those that were old, and track them after cell division.
The researchers observed that the various types of organelle were similarly distributed between the two daughters, with one exception. Organelles called mitochondria showed differential segregation, such that the multi-talented stem-cell daughter received most of the newly synthesized mitochondria, whereas the tissue-progenitor daughter received around six times more old mitochondria (Fig. 1). Thus, organellar rejuvenation occurs in tissue stem cells, and involves mitochondria.
Mitochondria use oxygen to burn fats, sugars and amino acids, generating ATP molecules that act as the cell's energy currency. This oxidative metabolism establishes an electric charge (a membrane potential) across the membrane surrounding the organelle3 that can be used as a measure of mitochondrial ATP synthesis. Oxidative metabolism also generates side products in the form of reactive oxygen species (ROS) — potent signalling molecules that, if produced in excess, can damage surrounding proteins, lipids and DNA. Subtle changes in ROS can modify stem-cell behaviour, promoting commitment to differentiation4. Indeed, mitochondrial dysfunction promotes stem-cell dysfunction and exhaustion, leading to premature signs of ageing that mimic physiological ageing5,6,7. By contrast, fully functional mitochondrial proteins minimize ROS production and maximize control over oxidative metabolism. It is therefore no surprise that stem cells treasure prime fitness in this organelle.
The concept of apportioning old mitochondria asymmetrically has already been established in baker's yeast, in which damaged proteins and mitochondria with lower oxidative function preferentially remain in the mother cell8,9, rather than entering the daughter that buds off from it. By contrast, Katajisto et al. found no functional differences between the mitochondria apportioned to the different daughter cells, because the membrane potential was similar in both types of cell. Even when the authors abolished the membrane potential, asymmetric apportioning occurred. In fact, the only determinant of mitochondrial fate was organellar age.
Katajisto and colleagues showed that ageing mitochondria were preferentially located close to the nucleus, whereas young organelles were also found in the cell periphery (Fig. 1). This suggests that physical segregation of the organelles contributes to differential delivery during cell division. Chemical inhibition of the fission process by which mitochondria divide hindered this compartmentalization, indicating a key role for mitochondrial dynamics in asymmetric mitochondrial segregation.
Asymmetric mitochondrial apportioning could be an indication of the general selfishness of stem cells — the cells that end up being mortal are largely unimportant compared with their immortal sisters. This hypothesis would be consistent with the 'disposable soma' theory of ageing10 (extended here to apply to tissue stem cells), which posits that an organism is merely disposable packing material for its germ cells. The second possibility, however, is that the committed daughter cell actually requires old mitochondria to fulfil its function. Mitochondrial ATP synthesis increases on differentiation, and an increase in ROS in response to increased mitochondrial function is associated with differentiation4. For example, in red blood cells, subtle increases in ROS orchestrate iron loading and cell maturation11. The asymmetric apportioning of mitochondria could therefore provide the ROS boost required to initiate a differentiation program.
The ultimate fate of old mitochondria during the differentiation of tissue-progenitor daughters remains an open question. Eventually they will be recycled, and new organelles will replace them. The authors noticed that asymmetric apportioning of mitochondria required the presence of parkin, a protein that marks mitochondria for recycling12. However, there were no apparent changes in recycling levels in daughter cells. Whether parkin has a role, for example, in the timing of degradation of the old organelles after division remains unknown.
Katajisto and colleagues' study raises questions about the role of mitochondrial quality control as a regulator of cell fate and behaviour. For instance, an exciting possibility is that the mechanism described is a general feature of stem cells. It will be interesting to investigate whether similar mechanisms are in place in mature tissues. Furthermore, it is unclear how stem cells would handle increased mitochondrial-protein damage in mitochondrial disorders.
Another avenue for study is what happens to mitochondrial DNA during asymmetric mitochondrial apportioning. And finally, do similar mechanisms apply in germ cells, providing the offspring with a fresh mitochondrial start? Defining the molecular mechanisms underlying this phenomenon will bring us a step closer to understanding the cellular recipe for immortality — the rejuvenation of energy metabolism.Footnote 1
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Proceedings of the National Academy of Sciences (2018)
Proteomics analysis for asymmetric inheritance of preexisting proteins between mother and daughter cells in budding yeast
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