Volume 28, No 6, Jun 2018
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 28 Issue 6, June 2018: 625-643
ORIGINAL ARTICLES
Switching off IMMP2L signaling drives senescence via simultaneous metabolic alteration and blockage of cell death
Lifeng Yuan 1,2 , Linhui Zhai 3 , Lili Qian 3 , De Huang 2 , Yi Ding 2 , Handan Xiang 2 , Xiaojing Liu 2 , J. Will Thompson 4 , Juan Liu 2 , Yong-Han He 5 , Xiao-Qiong Chen 5 , Jing Hu 2 , Qing-Peng Kong 5 , Minjia Tan 3 and Xiao-Fan Wang 1,2
1Graduate Program in Molecular Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA; 2Department of Pharmacology and Cancer Biology, Duke
University School of Medicine, Durham, NC 27710, USA; 3Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, Shanghai 201203, China; 4Proteomics and Metabolomics Shared Resource, Duke University School of Medicine, Durham, NC 27710, USA and 5
State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
Correspondence: Correspondence: Xiao-Fan Wang (xiao.fan.wang@duke.edu)
Cellular senescence is a fundamental cell fate playing a significant role throughout the natural aging process. However, the molecular determinants distinguishing senescence from other cell-cycle arrest states such as quiescence and post-mitotic state, and the specified mechanisms underlying cell-fate decisions towards senescence versus cell death in response to cellular stress stimuli remain less understood. Employing multi-omics approaches, we revealed that switching off the specific mitochondrial processing machinery involving the peptidase IMMP2L serves as the foundation of the senescence program, which was also observed during the mammalian aging process. Mechanistically, we demonstrate that IMMP2L processes and thus activates at least two substrates, mitochondrial metabolic enzyme glycerol-3-phosphate dehydrogenase (GPD2) and cell death regulator apoptosis-inducing factor (AIF). For cells destined to senesce, concerted shutdown of the IMMP2L-GPD2 and IMMP2L-AIF signaling axes collaboratively drives the senescent process by reprogramming mitochondria-associated redox status, phospholipid metabolism and signaling network, and simultaneously blocking cell death under oxidative stress conditions.
https://doi.org/10.1038/s41422-018-0043-5
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