An enzyme complex could stop cell aging

When the concern is expressed about cellular aging, it is associated with problems of age or youth, however, in scientific terms, the attention of specialists turns to other parallel consequences that the aging process triggers in cells and, consequently, in the general state of health and well-being of each individual.

In particular, the emphasis is on the value that cellular youth brings to health processes. In short, it is about understanding how the breakdown of their own cells affects people to trigger health consequences or not. Many diseases are generally produced by the decline or deterioration of the functioning of cells and as a result of disturbances in their normal functioning.

Researchers at the University of Montreal and McGill University in Canada have discovered a new multienzymatic complex that reprograms the metabolism and exceeds the cellular senescencia, a process by which cells age until they stop dividing but do not die. These findings pave the way for possible new cancer therapies, as published in the journal Molecular Cell. Along with oxidation, inflammation and epigenetic changes, another factor that brings together a whole series of alterations is cellular senescence. Cells can survive, die, or go into senescence. The balance of these processes ensures the stability of the organism.

An interdisciplinary working group pursued this discovery. For this task, it brought together representatives of entities such as the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Terry Fox Foundation, the CIBC Chair in Breast Cancer Research. , the Quebec-Health Research Fund, the Montreal Cancer Institute and the Institute of Natural Sciences and the Engineering Research Council of Canada.

In their paper, they raised the fundamental role of metabolic rewiring and redox balance, so called the chemical balance that occurs in a reduction-oxidation reaction in cancer. Cellular senescence, which involves the aging of cells until they stop dividing but do not die, is a barrier to the buildup of genetic mutations within cells that affect genes (tumorigenesis), a case avoided in cancer cells by little-known mechanisms.

Specialists have tried to present a multienzymatic complex that reprograms the metabolism from NAD (a complex which acts as a cofactor playing an essential role in many enzymatic reactions of energy metabolism, such as glycolysis, oxidative phosphorylation, oxidation of fatty acids) to NADP (a chemical compound present in the cells of muscle tissues of living things and which is of crucial importance in the processes of fatty alcohols, carbohydrates and proteins).

Scientists demonstrate through their research that an enzyme complex called HTC (hydride transfer complex) can inhibit the aging of cells. “HTC protects cells from hypoxia, a lack of oxygen that normally leads to deathPrincipal author reported Gerardo Ferbeyre, professor of biochemistry at UdeM and principal investigator at the Research Center of the University Hospital of Montreal.

“It is important to note that HTC can be sequestered by certain cancer cells to improve their metabolism, resist a hypoxic environment and proliferate,” said Ferbeyre, who made the discovery with Sebastián Igelmann, doctoral student in his lab and first author to study it.

HTC is composed of three enzymes: pyruvate carboxylase, malate dehydrogenase 1 and malic enzyme 1. All were present in excess in samples from a murine model of prostate cancer generated at the University of Veterinary Medicine in Vienna. , Austria, and tissue samples from prostate cancer patients.

“The most interesting thing is that inhibiting these enzymes stopped the growth of prostate cancer cells, suggesting that HTC could be a key target for developing new therapies for a variety of cancers, including prostate cancer, ”Ferbeyre said.

Most of the key metabolic cycles were identified over 50 years ago, but the HTC has remained hidden from researchers. “We found him doing cutting-edge metabolomic analysis, the study of chemical processes in cell metabolism,” said co-author Ivan Topisirovic, a McGill researcher and professor of medicine.

Scientists were able to assemble the enzyme complex from purified proteins and obtain biophysical data on its composition. His next step will be to generate a detailed high-resolution structure of the enzyme complex to design drugs capable of modulating its functions.

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