Editors' ChoiceApoptosis

Notch Protects the Mitochondria

Science Signaling  20 Apr 2010:
Vol. 3, Issue 118, pp. ec119
DOI: 10.1126/scisignal.3118ec119

Notch is a signaling molecule activated by cleavage of the ligand-bound receptor to produce the active Notch intracellular domain (NICD), which has well-known functions as a transcriptional regulator when translocated to the nucleus. Perumalsamy et al. provide evidence that NICD also functions at the mitochondria to preserve mitochondrial integrity under conditions that can trigger apoptotic cell death. Bax is a proapoptotic protein that associates with the mitochondria and when oligomerized contributes to loss of mitochondrial function and mitochondrial fragmentation. With transfected cells, the authors showed that expression of NICD, but not a nuclear-restricted form, prevented Bax-mediated apoptosis (overexpression of Bax with or without the nonspecific kinase inhibitor staurosporine, depending on the cell type). NICD appeared to act very early in the process, because NICD prevented changes in Bax conformation (detected with a conformation-specific antibody) and Bax oligomerization (detected by immunoblotting, with crosslinking agents, or by monitoring Bax mobility) and preserved the mitochondrial network and outer mitochondrial membrane integrity (detected by fluorescence analysis). Knockdown of protein involved in NICD-mediated transcriptional responses failed to prevent the antiapoptotic actions of overexpressed NICD. However, the antiapoptotic activity of NICD was blocked in cells in which Akt was knocked down or in cells expressing a dominant-negative form of Akt, suggesting that Akt is part of the NICD survival pathway. The survival activity of NICD was also blocked by knocking down mitofusins 1 or 2, suggesting that NICD may regulate mitochondrial fusion. The authors confirmed that pharmacological inhibition of Notch cleavage promoted death of T cells with characteristics similar to those following cytokine withdrawal—Bax dimerization and conformational change. Furthermore, expression of NICD in T cells, which prevents death from cytokine withdrawal, prevented Bax activation. Thus, NICD appears to have a survival function that does not involve its transcriptional regulatory activity.

L. R. Perumalsamy, M. Nagala, A. Sarin, Notch-activated signaling cascade interacts with mitochondrial remodeling proteins to regulate cell survival. Proc. Natl. Acad. Sci. U.S.A. 107, 6882–6887 (2010). [Abstract] [Full Text]