Faced with a lack of ATP from mitochondria, the cell nucleus can start its own mechanisms for the synthesis of these molecules.
Spanish biologists have identified key details of how this "alternative energy source" works and identified its most important proteins. This is described in an article published by the journal Science.
The total length of DNA in each cell of the human body is approximately 2 m, and it is impossible to place it in the nucleus without a complex and dense packing. At the same time, many DNA-related processes, including replication, repair, and regulation of gene activity, require the "unpacking" of chromatin and the action of proteins that consume energy in the form of ATP molecules. ATP is synthesized by mitochondria (less often and in small quantities, they are formed during glycolysis reactions in the cytoplasm).
However, with a massive rearrangement of chromatin, the problem of delivering the required amounts of ATP into the nucleus arises. Therefore, more than half a century ago, it was assumed that the nucleus has its own mechanisms for the synthesis of ATP molecules. This is also demonstrated by new work carried out by Spanish biologists under the direction of Miguel Beato of the Barcelona Institute of Science and Technology (BIST).
The authors experimented on a culture of breast tumor cells. They measured the ratio of ATP to ADP ("used" energy carrier molecules) in different parts of the cell: in the mitochondria, in the cytosol and in the nucleus. By blocking the production of ATP in the mitochondria, scientists have shown that the nucleus quickly depletes the accumulated reserves of ATP. However, under the conditions of the need for a serious rearrangement of chromatin (with the addition of a progestin, which stimulates profound changes in cellular metabolism), the ATP content in the nucleus continued to grow, despite the fact that mitochondria no longer replenished their supply.
The source of ATP in the nucleus is poly- (ADP-ribose) (poly- (ADP-ribose), PAR), which is used here, in particular, to regulate the activity of individual enzymes. PARG hydrolysis to individual monomers is carried out by the PARG protein. In the presence of pyrophosphates, NUDIX5 hydrolase catalyzes their conversion to ATP. Miguel Beato and colleagues showed that inhibition of any of these proteins prevents the accumulation of ATP in the nuclei of cells, even those treated with progestin, and leads to a sharp slowdown in the processes requiring chromatin rearrangement.
At the same time, the authors noted that both enzymes exhibit increased activity in cancer cells. This suggests that genome rearrangements occurring in a tumor require active synthesis of ATP within the cell nuclei, and makes NUDIX5 a promising target for the creation of new anticancer drugs.
Roman Fishman
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