A healthy adult must produce 100 billion new red blood cells every day to maintain the number of red blood cells in his blood circulation. A team of researchers from the Federal Institute of Technology in Lausanne (EPFL) has identified a key step in the process of red blood cell production. This research may not only help elucidate the causes of blood diseases such as anemia, but also bring doctors ’dreams closer to reality: they can make red blood cells in the laboratory, thus providing a potential inexhaustible The main component resources of blood are used for blood transfusion.
The essence of red blood cells is a bag of hemoglobin that transports oxygen to the whole body. Its life begins with hematopoietic stem cells in the bone marrow, and after a highly controlled proliferation and differentiation process, it obtains its final identity.
A key step in this differentiation process is mitophagy. As the mitochondria are depleted, the cell's hemoglobin load capacity reaches its maximum. However, until now, the mechanism controlling mitochondrial autophagy has not been clearly understood.
In a paper published this week in the journal Science, Isabelle Barde of the Federal Institute of Technology in Lausanne and colleagues confirmed through experiments that KRAB-type zinc finger proteins and KAP1 cofactors work synergistically in a sophisticated and complex manner Regulated mitochondrial autophagy.
The senior author and virologist DidierTrono has been interested in the KRAB / KAP1 system for many years. As we all know, it has played a role in "silencing" the reverse transcription factor elements of the mammalian genome for 350 million years. They were initially retroviruses that could be integrated into the genetic code of the infected organism. "It's doing such a good job that it has been assigned many other things during evolution," Trono said.
One of the responsibilities of the KRAB / KAP1 system is to regulate mitochondrial autophagy. The researchers found that mice genetically engineered to lack KAP1 quickly became anemia because they were unable to produce red blood cells. More specifically, they found that the stem cell differentiation process stops at the stage of mitochondrial degradation in erythroblasts (erythroblast precursors). And knocking out KAP1 in human blood cells will also produce a similar effect, indicating that its role in regulating mitochondrial autophagy is conserved throughout the evolution from mice to humans.
The researchers further proved that the KRAB / KAP1 system works by inhibiting mitochondrial autophagy repressors. In other words, just as negative to positive, it activates this target process. This indicates that mutations of various elements in this regulatory system may cause blood diseases such as anemia and certain types of leukemia, which in turn points out the future therapeutic targets of these diseases. It also points out the possibility of simulating the synthesis of red blood cells in the laboratory.
But these research findings have broader significance. Although mitochondria are essential for the normal function of many cells, if they produce destructive free radicals (a by-product of cellular respiration in some cases), they can also be fatal to cells. The oxidative stress caused by these free radicals is associated with liver disease, heart disease and obesity. Therefore, understanding the controlled mechanism of mitochondrial autophagy may lead to a better understanding and treatment of these diseases.
Trono believes that this multi-level combination regulation rule may be applicable to a wide range of physiological systems. "It gives an extremely high level of modularity to the natural completion of physiological activities." He likens it to the way the organ runs.
Each organist has a keyboard and foot pedals under his control. He uses them in various combinations to adjust the sound produced by the instrument. Similarly, fine-tuning one or several control elements can have significant effects in many biological processes. Although any one of the elements may cause a failure, but due to the small contribution of each, the damage is often limited. In turn, this gives the system stability. Trono believes that this stability has been selected and improved by evolution for hundreds of millions of years.
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