Greek scientists have revealed a new molecular mechanism that regulates aging and reproduction

Recent research at the Institute of Molecular Biology and Biotechnology (IMBB) of the Technology and Research Foundation (ITE) of the University of Crete sheds light for the first time on a fundamental control mechanism of cell aging and reproductive fertility.

IMBB researchers Dr. Margarita Elena Papandreou and Dr. George Konstantinidis, led by Dr. Nektarios Tavernarakis, (Professor of the School of Medicine of the University of Crete and President of ITE) revealed a new molecular mechanism that works in cells to preserve the integrity and function of the nucleus, and regulates the somatic as well as the reproductive aging.

The nucleus is the central organelle of eukaryotic cells, where the genetic material is located, or otherwise, the DNAwhich determines cellular identity and function in all organisms.

The structure and architecture of the nucleus changes dramatically during aging, but also during carcinogenesis. Additionally, a common feature of aging, the pathological conditions associated with it, but also progeroid syndromes (eg, Hutchinson-Gilford, Werner, Bloom, Cockayne syndromes, and others), are the lesions located in the nucleus of cell, a structure inside the nucleus that controls production ribosomes which function as the protein synthesis machines of the cells.

It is worth noting that maintaining the integrity of the nucleus and nucleus accumbens has been associated with longevity, and with life-prolonging interventions in experimental animals. However, the molecular and cellular mechanisms that monitor and ensure the structure of the nucleus and nucleolus remain elusive. It is also not known whether the progressive degeneration of nuclear architecture seen in aging and in age-related diseases is a consequence, or a mere consequence, of these conditions, or a major contributor to the aging process and pathogenesis. of progeroid syndromes.

The study

Using two experimental organisms, the nematode Caenorhabditis elegans and the mouse, IMBB-ITE researchers studied these fundamental questions. Maintenance of nuclear structure and function requires the continuous and tightly regulated recycling of defective or damaged nuclear components. Targeting and degradation of damaged nuclear components is accomplished by a selective type of autophagy, nucleophagy, which serves as a control mechanism of nuclear homeostasis. Maintenance of nuclear morphology and recycling of nuclear material are essential for cell function. Problems in proper nucleophagy have been implicated in a wide range of pathological conditions, including DNA damage, cancer, and neurodegenerative diseases. However, it remained unknown how nucleophagy is regulated, as well as the effects of its deregulation on aging.

The study published today reveals a key mechanism for its regulation nuclear eating. In particular, the giant anchoring protein of the nuclear envelope, ANC-1 in the nematode, and its counterpart Nesprin 2 in mice, act as specific regulators of nucleophagy. In fact, it is remarkable that the levels of these proteins are appropriately modulated through autophagy. The ANC-1/Nesprin 2 protein is found in the outer membrane of the nucleus of all cells, and its mutations have been found to be involved in neurodegenerative diseases, cardiomyopathies and cancer in humans. By controlling the selective degradation of core and nucleolus components, the ANC-1/Nesprin 2 protein ensures the shielding of cell homeostasis, resistance to stressors and the significant increase in life expectancy of the organism. Furthermore, ANC-1/Nesprin 2-mediated nucleophagy contributes as a quality control mechanism to the clearance of dysfunctional progenitor germ cells during their differentiation in the nematode reproductive system. Disruption of this clearance process causes tumors in the C. elegans reproductive system, and progressive sterility. This is a mortality phenomenon of the germ cell line that is required for the reproduction of all animal organisms and is, normally, immortal. Similarly, inactivation of the Nesprin 2 protein in female mice causes ovarian carcinoma, while polymorphisms in the corresponding human protein, Syne2, have been linked to infertility in women.

“One of the most fascinating puzzles of modern biomedical research is understanding the molecular basis of two diametrically opposed, fundamental phenomena in biology: the mortality of the body and the immortality of the so-called germ cell line, that is, the cells of the reproductive system that ensure reproduction .The prospect of uncovering the mechanism responsible for this highly idiosyncratic character of cell types, within the same organism, was a strong motivation for us to attempt to answer this important question. We decided to focus on nuclear morphology. , which deteriorates in somatic cells during senescence, while, in contrast, remains unchanged in the germ cell line.We hypothesized that a highly efficient homeostatic mechanism maintains germ cell nuclear structure while failing to do the same in somatic cells. cells of the body, vs aging. We were surprised to find that a special autophagy process, nucleophagy, is a central factor in maintaining the architecture of the nucleus, recycling nuclear material, while limiting the increase in nucleolus size observed during aging. It is also interesting that nucleophagy itself is regulated by signaling pathways and interventions, such as those of insulin and caloric restriction, that determine lifespan in many different organisms, from nematodes to mammals. This highlights the pivotal position of nucleophagy, as a point of convergence of molecular and cellular processes affecting aging,” said Professor Nektarios Tavernarakis.

The results of the research of IMBB-ITE scientists highlight nucleophagy as a central molecular mechanism, through which the long-term maintenance of nuclear architecture and homeostasis is ensured. Members of the ANC-1/Nesprin family of proteins have a key regulatory role in nucleophagy. The recycling of nuclear material through nucleophagy contributes to the longevity of somatic cells, while ensuring the immortalization of germline cells of the reproductive system, and, by extension, reproductive health. The fact that the molecular mechanisms controlling nucleophagy have been evolutionarily conserved among very different organisms suggests that corresponding processes govern aging and reproduction in humans. These findings are expected to be used to treat diseases characterized by the collapse of the nuclear architecture, as well as human infertility.

RES-EMP

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