Aging-associated increase in Golgi stress disturbs cellular signaling and epigenetic regulation

The process of aging is associated with disturbed mineral homeostasis, such as zinc deficiency. Simultaneously, cellular response to external stimuli, including receptor signaling and DNA repair response diminishes, and epigenetic dysregulation occurs. The Golgi apparatus plays various roles in the cell; however, the effect of aging on the morphology and function of the Golgi apparatus and the impact of Golgi senescence in cellular activity remains unknown. In the present study, we found that Golgi stress is associated with senescent cell irresponsiveness to external stimuli. The senescent Golgi was associated with a disassembled microtubule network in the Golgi and perinuclear areas. These effects could be reproduced by disruption of the Golgi-associated microtubules or zinc depletion. To clarify the importance of Golgi-zinc homeostasis in more detail, the implications of the Golgi-zinc transporter ZIP13 were analyzed; Zip13-deficient mice Golgi exhibited morphology similar to that of senescent Golgi. Additionally, fibroblasts from Zip13-deficient mice showed dysregulation of DNA repair and cellular acetylation with downregulated nuclear translocation of p300, HDAC1/2, and p53 proteins, which are reminiscent characteristics of senescent cells. Our findings demonstrate the underlying reason for senescent cell irresponsiveness to various stimuli and highlight the importance of a zinc-rich diet during aging. To investigate the influence of local zinc homeostasis on the structures of the Golgi and perinuclear region, we performed gene expression profiling of fibroblasts from wildtype and Zip13-/- mice. Gene expression profiles of wildtype and Zip13-/- cells were generated using the Affymetrix GeneChip Mouse Gene 2.0 ST Array (Affymetrix, Santa Clara, CA, USA).