Calcium transferring from ER to mitochondria via miR-129/ITPR2 axis controls cellular senescence in vitro and in vivo

  • Mech Ageing Dev. 2024 Jan 11:111902. doi: 10.1016/j.mad.2024.111902.
Yue Gao  1 ,  Lei Xu  2 ,  Yaru Li  2 ,  Dandan Qi  2 ,  Chaofan Wang  2 ,  Changjiao Luan  3 ,  Shihui Zheng  4 ,  Qiu Du  2 ,  Weili Liu  2 ,  Guotao Lu  5 ,  Weijuan Gong  6 ,  Xingjie Ma  7
Affiliations
  • 1. Department of The Central Laboratory, Department of Intensive Care, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China; Department of Pathology, Northern Jiangsu People's Hospital, Yangzhou, China.
  • 2. Department of The Central Laboratory, Department of Intensive Care, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China.
  • 3. Department of The Central Laboratory, Department of Intensive Care, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China; Department of Lung, The Third People's Hospital of Yangzhou, Yangzhou, China.
  • 4. Department of Molecular Biology, Inter faculty Institute of Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany.
  • 5. Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China.
  • 6. Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China. Electronic address: [email protected].
  • 7. Department of The Central Laboratory, Department of Intensive Care, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China. Electronic address: [email protected].
PMID: 38218462 DOI: 10.1016/j.mad.2024.111902
Abstract

Senescent cells are known to be accumulated in aged organisms. Although the two main characteristics, cell cycle arrest (for dividing cells) and secretion of senescence-associated secretory phenotype (SASP) factors, have been well described, the lack of sufficient senescent markers and incomplete understanding of mechanisms have limited the progress of the anti-senescence field. Calcium transferred from the endoplasmic reticulum (ER) via inositol 1, 4, 5-trisphosphate receptor type 2 (ITPR2) to mitochondria has emerged as a key player during cellular senescence and aging. However, the internal regulatory mechanisms, particularly those of endogenous molecules, remain only partially understood. Here we identified miRNA-129 (miR-129) as a direct repressor of ITPR2. Interestingly, miR-129 controlled a cascade of intracellular calcium signaling, mitochondrial membrane potential (MMP), Reactive Oxygen Species (ROS), DNA damage, and consequently cellular senescence through ITPR2 and mitochondrial calcium uniporter (MCU). In addition, miR-129 was repressed in different senescence models and delayed bleomycin-induced cellular senescence. Importantly, intraperitoneal injection of miR-129 partly postponed bleomycin-accelerated lung aging and natural aging markers as well as reduced immunosenescence markers in mice. Altogether, these findings demonstrated that miR-129 regulated cellular senescence and aging markers via intracellular calcium signaling by directly targeting ITPR2.

Keywords
ITPR2; MCU; calcium signaling; cellular senescence; miR-129.
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