Age-associated interplay between zinc deficiency and Golgi stress hinders microtubule-dependent cellular signaling and epigenetic control

Sofia Brito; Hyojin Heo; Jinyoung Kim; Byungsun Cha; Youngdo Jeong; Wooseon Choi; Chandani Shrestha; Gang Hyoung Lee; Sun Ju Park; Ki Bok Yoon; Kentaro Oh-Hashi; Sung Tae Kim; Sehyun Chae; Sung Kweon Cho; Byung Mook Weon; Jiyoon Kim; Bum-Ho Bin

doi:10.1016/j.devcel.2024.12.024

Age-associated interplay between zinc deficiency and Golgi stress hinders microtubule-dependent cellular signaling and epigenetic control

Dev Cell. 2024 Dec 30:S1534-5807(24)00763-9. doi: 10.1016/j.devcel.2024.12.024. Online ahead of print.

Authors

Sofia Brito¹, Hyojin Heo², Jinyoung Kim³, Byungsun Cha², Youngdo Jeong⁴, Wooseon Choi³, Chandani Shrestha³, Gang Hyoung Lee², Sun Ju Park², Ki Bok Yoon², Kentaro Oh-Hashi⁵, Sung Tae Kim⁶, Sehyun Chae⁷, Sung Kweon Cho⁸, Byung Mook Weon⁹, Jiyoon Kim¹⁰, Bum-Ho Bin¹¹

Affiliations

¹ School of Advanced Materials Science & Engineering, Sungkyunkwan University, Suwon 16419, South Korea; Research Center for Advanced Materials Technology, Sungkyunkwan University, Suwon 16419, South Korea.
² Department of Biological Sciences, Ajou University, Suwon 16499, South Korea.
³ Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea; Department of Medical Sciences, Graduate School, The Catholic University of Korea, Seoul 06591, South Korea.
⁴ Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, South Korea; Department of HY-KIST Bio-convergence, Hanyang University, Seoul 04763, South Korea.
⁵ Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; Center for One Medicine Innovative Translational Research (COMIT), Institute for Advanced study, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
⁶ Department of Pharmaceutical Engineering, Inje University, Gimhae 50834, South Korea; Department of Nanoscience and Engineering, Inje University, Gimhae 50834, South Korea.
⁷ Division of Chemical Engineering and Bioengineering, College of Art, Culture and Engineering, Kangwon National University, Chuncheon 24341, South Korea; Multidimensional Genomics Research Center, Kangwon National University, Chuncheon 24341, South Korea.
⁸ Department of Pharmacology, Ajou University School of Medicine, Suwon 16499, South Korea.
⁹ School of Advanced Materials Science & Engineering, Sungkyunkwan University, Suwon 16419, South Korea; Research Center for Advanced Materials Technology, Sungkyunkwan University, Suwon 16419, South Korea. Electronic address: bmweon@skku.edu.
¹⁰ Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea; Department of Medical Sciences, Graduate School, The Catholic University of Korea, Seoul 06591, South Korea; Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea. Electronic address: jykim@catholic.ac.kr.
¹¹ Department of Biological Sciences, Ajou University, Suwon 16499, South Korea. Electronic address: bhb@ajou.ac.kr.

PMID: 39765234
DOI: 10.1016/j.devcel.2024.12.024

Abstract

Golgi abnormalities have been linked to aging and age-related diseases, yet the underlying causes and functional consequences remain poorly understood. This study identifies the interaction between age-associated zinc deficiency and Golgi stress as a critical factor in cellular aging. Senescent Golgi bodies from human fibroblasts show a fragmented Golgi structure, associated with a decreased interaction of the zinc-dependent Golgi-stacking protein complex Golgin45-GRASP55. Golgi stress is increased, and functions such as glycosylation and vesicle transport are impaired. These disturbances promote Golgi and perinuclear microtubule disassembly and subsequent mislocalization of intracellular proteins associated with cellular signaling and epigenetic control. Pharmacological induction of Golgi stress or zinc deficiency, or ablation of the Golgi-associated zinc transporter gene Zip13 in mouse fibroblasts, replicate the characteristics of cellular senescence, emphasizing the critical role of Golgi-zinc homeostasis. These findings highlight the importance of adequate zinc intake and suggest targeting Golgi dysfunction as a therapeutic strategy for alleviating age-related cellular decline.

Keywords: GRASP55; Golgi; ZIP13; aging; epigenetics; microtubules; senescence; signaling; zinc; zinc transporter.