IMBB researchers uncover a new molecular mechanism that regulates aging and reproduction, making a critical contribution to the protection and long-term maintenance of the structure and function of the cell nucleus.

In particular, a recent study at the Institute for Molecular Biology and Biotechnology (IMBB) of the Foundation for Technology and Research (ITE), whose results are published today in the prestigious international scientific journal Nature Aging, sheds light for the first time on a fundamental mechanism for controlling aging and reproductive fertility. IMBB researchers Dr. Margarita Elena Papandreou and Dr. George Constantinidis led by Dr. Nektarios Tavernarakis (Professor at the Faculty of Medicine at the University of Crete and President of ITE) discovered a new molecular mechanism that works in cells to maintain the integrity and function of the nucleus and regulates physical as well as reproductive aging.

Common feature of aging

The nucleus is the central organelle of eukaryotic cells that contains the genetic material, or DNA, that determines the cellular identity and function of all organisms. The structure and architecture of the nucleus change dramatically with aging, as well as during carcinogenesis. In addition, a common feature of aging, associated pathological conditions, and progeroid syndromes (eg, Hutchinson-Gilford, Werner, Bloom, Cockayne, and others) are lesions located in the cell nucleus, a structure within the nucleus that controls the production of ribosomes. , which act as machines for protein synthesis in the cell. 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 control and maintain the structure of the nucleus and nucleolus remain unclear. It is also not known whether the progressive degeneration of nuclear architecture seen with aging and age-related diseases is a consequence or a simple consequence of these conditions or a major factor influencing the aging process and the pathogenesis of progeroid syndromes.

experimental organisms

Using two experimental organisms, the nematode Caenorhabditis elegans and a mouse, the IMBB-ITE researchers explored these fundamental questions. Maintaining nuclear structure and function requires continuous and highly regulated recycling of defective or damaged nuclear components. Targeting and degradation of damaged nuclear components is carried out by a selective type of autophagy, nucleophagy, which serves as a mechanism for controlling nuclear homeostasis. The maintenance of nuclear morphology and the processing of nuclear material are necessary for the functioning of cells. Problems with proper nucleophagy are associated with 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 impact of its deregulation on aging.

nuclear eating

A study published today reveals a key mechanism for the regulation of nucleophagy. In particular, the giant nuclear envelope anchor protein, ANC-1 in nematodes, 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 properly modulated through autophagy. The ANC-1/Nesprin 2 protein is found in the outer nuclear membrane of all cells, and its mutations have been found to be associated with neurodegenerative diseases, cardiomyopathies, and cancer in humans. By controlling the selective degradation of the components of the nucleus and nucleolus, the ANC-1/Nesprin 2 protein provides shielding of cell homeostasis, resistance to stressors, and a significant increase in the lifespan of the organism. In addition, ANC-1/Nesprin 2 mediated nucleophagy as a quality control mechanism contributes to the removal of dysfunctional germline progenitor cells during their differentiation in the nematode reproductive system. Disruption of this clearance process causes tumors in the C. elegans reproductive system and progressive infertility. This is the death of the germ cell line, which is necessary 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 of the corresponding human Syne2 protein are associated with female infertility.

“One of the most exciting mysteries 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 ensures reproduction. The prospect of discovering the mechanism responsible for such a peculiar character of cell types within the same organism has prompted us to try to answer this important question. We decided to focus on nuclear morphology, which deteriorates in somatic cells with aging, while, on the contrary, remains unchanged in the germline. We hypothesized that a highly efficient homeostatic mechanism maintains the structure of the germ cell nucleus, but cannot do the same in the body’s somatic cells during aging. We were surprised to find that a specific autophagy process, nucleophagy, is a central factor in maintaining nuclear architecture, recycling nuclear material while limiting the increase in nucleolus size seen with aging. It is also interesting that nucleophagy itself is regulated by signaling pathways and interventions such as insulin and calorie restriction that determine lifespan in many different organisms, from nematodes to mammals. This highlights the key position of nucleophagy as a confluence point for molecular and cellular processes that influence aging,” said Professor Nektarios Tavernarakis.

The results of the IMBB-ITE study highlight nucleophagy as the central molecular mechanism by which the long-term maintenance of nuclear architecture and homeostasis is ensured. Members of the ANC-1/Nesprin family of proteins play a key regulatory role in nucleophagy. The processing of nuclear material through nucleophagy promotes the longevity of somatic cells, ensuring the immortalization of the germ cells of the reproductive system and, as a result, reproductive health. The fact that the molecular mechanisms that control nucleophagy have been evolutionarily conserved among very different organisms suggests that the relevant processes govern aging and reproduction in humans. It is expected that these results will be used to treat diseases characterized by the collapse of the nuclear architecture, as well as human infertility.

Source: RES-IPE