Switching off IMMP2L signaling drives senescence via simultaneous metabolic alteration and blockage of cell death.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Yuan, L; Zhai, L; Qian, L; Huang, D; Ding, Y; Xiang, H; Liu, X; Thompson, JW; Liu, J; He, Y-H; Chen, X-Q; Hu, J; Kong, Q-P; Tan, M; Wang, X-F

Published Date

  • June 2018

Published In

Volume / Issue

  • 28 / 6

Start / End Page

  • 625 - 643

PubMed ID

  • 29808012

Pubmed Central ID

  • PMC5993829

Electronic International Standard Serial Number (EISSN)

  • 1748-7838

Digital Object Identifier (DOI)

  • 10.1038/s41422-018-0043-5


  • eng

Conference Location

  • England