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

Abstract

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.

IMMP2L: a mitochondrial protease suppressing cellular senescence

“…5 In the muscle from aged normal mice, as well as in peripheral blood from fragile old humans, IMMP2L was diminished (while CDKN2A protein was increased) as compared to young controls. 4 More importantly, deletions of intron 3 of IMMP2L were less frequent in centenarians than in unrelated control individuals, indicating that longevity is associated with genomic integrity of the IMMP2L locus . 4 All these findings argue in favor of the conjecture that organismal aging and cellular senescence are coupled to the downregulation or inhibition of IMMP2L (Fig.…”

“…4 More importantly, deletions of intron 3 of IMMP2L were less frequent in centenarians than in unrelated control individuals, indicating that longevity is associated with genomic integrity of the IMMP2L locus . 4 All these findings argue in favor of the conjecture that organismal aging and cellular senescence are coupled to the downregulation or inhibition of IMMP2L (Fig. 1).…”

“…4 Indeed, in normal bronchial epithelial cells, induction of senescence by blockade of epidermal growth factor receptor was linked to the transcriptional upregulation of SERPINB4, and SERPINB4 knockdown could prevent senescence in this model, while its overexpression was sufficient to trigger senescence. 4 Similarly, knockdown of IMMP2L, which turned out to be the principal target of SERPINB4, stimulated the senescent program in various human cell types in vitro 4, echoing the prior observation that mice bearing a mutation in the IMMP2L locus display a progeroid (early aging) phenotype. 5 In the muscle from aged normal mice, as well as in peripheral blood from fragile old humans, IMMP2L was diminished (while CDKN2A protein was increased) as compared to young controls.…”

“…In a recent paper in Cell Research, Yuan et al 4 reveal the surprising finding that one major mechanism leading to senescence may consist in the shut down of inner mitochondrial membrane peptidase subunit 2 (IMMP2L), through downregulation of protein expression or inactivation by an endogenous clade B serine protease inhibitor named SERPINB4. 4 Indeed, in normal bronchial epithelial cells, induction of senescence by blockade of epidermal growth factor receptor was linked to the transcriptional upregulation of SERPINB4, and SERPINB4 knockdown could prevent senescence in this model, while its overexpression was sufficient to trigger senescence. 4 Similarly, knockdown of IMMP2L, which turned out to be the principal target of SERPINB4, stimulated the senescent program in various human cell types in vitro 4, echoing the prior observation that mice bearing a mutation in the IMMP2L locus display a progeroid (early aging) phenotype.…”

“…By which mechanism can IMMP2L suppress senescence? Through a series of elegantly conducted experiments, Yuan et al 4 demonstrate that, in non-senescent cells, IMMP2L assures the proteolytic maturation of two major substrates, namely glycerol-3-phosphate dehydrogenase 2 (GPD2), a metabolic enzyme, and apoptosis-inducing factor (AIF), a redox-active flavoprotein that contributes to the biogenesis of the respiratory chain complex I, but also has a potentially lethal function. 6,7 After its processing by IMMP2L, GPD2 locates at the inner mitochondrial membrane where it catalyzes the conversion of glycerol-3-phosphate (G3P) to dihydroxyacetone phosphate (DHAP).…”