Age-associated increase of Golgi stress Disturbs microtubule assembly and nuclear translocation

Abstract

Aging is a complex biological process characterized by a progressive decline in cellular responsiveness to various stimuli. As ageing progresses, the body's mineral homeostasis breaks down and phenomena such as zinc deficiency occur. At the same time, cellular responses to external stimuli, such as receptor signaling and DNA repair responses, decrease and epigenetic dysregulation occurs. Recent studies have provided important insights into the interactions and changes in the cytoplasm and nucleus associated with the aging process and have shown that cytoplasm-to-nucleus translocation is inhibited, but the underlying mechanisms remain unclear. Golgi is a densely packed membrane organelle in the perinuclear region that serves as a hub for the trafficking of proteins and lipids and the post-translational modification of cargoes prior to final delivery. However, it is still unclear how Golgi changes during aging. In this study, we found that senescent Golgi exacerbates the unresponsiveness of senescent cells to external stimuli. Senescent Golgi results in impairment of classical Golgi functions, including proteolysis of CREB3 and glycosylation of the hepatic zinc transporter ZIP14, leading to a defective Golgi stress response and abnormal zinc distribution in the body. This altered Golgi morphology is associated with disassembly of the Golgi-microtubule network, resulting in impaired cellular responses, and disrupted nuclear translocation of key regulatory proteins such as p53, p300, and HDAC1/2. To delve deeper into the importance of Golgi zinc homeostasis, we analyzed the implications of the Golgi zinc transporter ZIP13. We found that mice lacking ZIP13 exhibit a fragmented Golgi architecture, resulting in disrupted nuclear protein translocation. This dysregulation is associated with impaired DNA repair and acetylation, reminiscent of the characteristics of senescent cells. These results highlight the importance of maintaining proper zinc distribution during the aging process for Golgi homeostasis.