We divide the mitochondria fairly
In order for a cell to become a stem cell, it must get newer mitochondria
Yulia Kondratenko, "Biomolecule"
"All the best for the children who will reproduce," the stem cell seems to say and gives newer (that is, more "healthy") mitochondria to the daughter cell, which will also become a stem cell. Well, the second daughter cell, which will follow the path of specialization, will not be too active anyway, so it gets older mitochondria.
Most cells in our body are specialized, tailored to perform a specific task: retinal cells capture light and transmit signals to the brain, striated muscle cells contract and relax when needed, gland cells synthesize specific molecules and send them to the rest of the cells. Such specialist cells should not and cannot divide. However, the body constantly needs new cells, and they are obtained as a result of the division of special cells intended for reproduction – stem cells.
When a stem cell divides, one new stem cell and one cell are formed, from which a new "specialist" will develop. The new stem cell will eventually repeat the fate of the "parent" – it will divide again, and the "specialist" will begin to perform its specific duties. Scientists have discovered that part of the inheritance of the maternal cell (a stem-like cell of the human breast epithelium) is divided between daughter cells in different ways. A cell that becomes a stem cell receives newer mitochondria than a sister doomed to specialization [1]. There were no differences in the inheritance of other components.
To observe how a stem cell distributes different components between daughter cells with different destinies, scientists created cells with photoactivated green fluorescent protein (paGFP) in various organelles [2]. This protein could be made to glow with a flash of ultraviolet light.
All organelles with paGFP that were present in the cell at the time of the flash fluoresced, but those that were formed after did not (paGFP was also synthesized in them, but after the flash, and therefore it did not glow). The scientists saw that old and new ribosomes, lysosomes, Golgi apparatus and chromatin were distributed evenly among the descendants of the stem cell: two daughter cells received the same amounts of green "old" and unpainted "new" components.
But for mitochondria, under certain conditions, differences were found. If the ultraviolet flash occurred less than 10 hours before cell division, then mitochondria, like other cellular organelles, were distributed evenly. If more than 10 hours passed from the moment of outbreak to division, then the labeled organelles turned out to be old enough for the cell to distribute them equally among the descendants.
The daughter cell, which was destined to become a stem cell, received much fewer old mitochondria than the cell that was supposed to become a "specialist" (see figure). This seems unfair, but in fact it is quite reasonable – after all, the specialist cell will no longer have to divide, and the stem cell has yet to give rise to many generations of other cells. Therefore, she gets newer mitochondria ("factories" that produce energy), in which, most likely, less damage has accumulated.
Uneven distribution of "old" mitochondria between two descendants of a stem cell. On the left – the mother cell an hour before division, on the right – the offspring an hour after division. Almost all the old mitochondria (the protein of their outer membrane Omp25, cross–linked with paGFP, fluoresces green) got only one of the daughter cells (P1) - the one that will follow the path of specialization. And the new stem cell (P2) almost didn't get the old mitochondria. Cell membrane lipids labeled with PKH26 dye fluoresce red – unlike mitochondria, they are distributed evenly between daughter cells. Figure from [1].
After that, the scientists used a different technique with two labels of different colors to fluoresce both old and new mitochondria. It turned out that the old mitochondria are located unevenly in the maternal stem cell: there are more of them closer to the nucleus, and, in addition, they form clusters. The mitochondria of the nucleus, apparently, are not only old, but also not very "healthy": the membrane potential, which is necessary for their functioning, is lower in such organelles.
It has been observed that the value of the mitochondrial membrane potential positively correlates with the severity of the "stem" properties of cells, so it would not be surprising that mitochondria with a higher potential (that is, newer ones) go to the daughter cell that will become a stem cell. Scientists "reset" the membrane potential of all mitochondria of stem cells to check whether mitochondria are not asymmetrically segregated based on the potential. However, depolarization did not affect the "age-dependent" distribution of mitochondria in daughter cells in any way. It turns out that the cell focuses only on the age of the mitochondria, and not on their membrane potential.
Interestingly, however, the cells that received new mitochondria with a knocked-down potential had less pronounced stem properties (for example, such cells less often formed spherical clusters characteristic of stem cells). It turns out that the membrane potential of mitochondria is important for the formation of "stemness", but the maternal stem cell, when distributing mitochondria, focuses not on it, but on the age of these organelles. It is important that only stem cells sorted mitochondria by age, and in differentiated cells older and newer mitochondria were mixed in the cytoplasm.
To maintain such an uneven distribution of old and new mitochondria in the stem cell, the protein Drp1 (dynamin-like protein 1) is needed. It participates in the degradation of old mitochondrial material, thus ensuring quality control of these organelles. If the work of this protein was inhibited, the old and new mitochondria in the cell were mixed. At the same time, the balance was disturbed among the descendants of such cells – fewer cells were formed, which received mainly new mitochondria. But even in those cells that were lucky enough to get mostly new mitochondria, the stem properties were less pronounced.
Interestingly, stem properties deteriorated in the descendants of cells with mixed mitochondria, although they themselves were not affected by the Drp1 inhibitor. It turns out that one violation of the distribution of mitochondria in a stem cell is enough to worsen the "stemness" of its descendants. Therefore, the stem cell really needs to maintain order in its mitochondrial networks by conducting their regular sanitation – in order to supply one of the daughter cells, which will continue to multiply, with the best mitochondria.
Literature
- Katajisto P., Dohla J., Chaffer C., Zoncu R., Chen W., Weinberg R. A. (2015). Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science. 348 (6232), 340–343;
- Biomolecule: "Fluorescent proteins: more diverse than you thought!".
Portal "Eternal youth" http://vechnayamolodost.ru21.05.2015