Stressed to death: Mitochondrial stress responses connect respiration and apoptosis in cancer

Abstract

Mitochondrial energetics and respiration have emerged as important factors in how cancer cells respond to or evade apoptotic signals. The study of the functional connection between these two processes may provide insight into following questions old and new: how might we target respiration or downstream signaling pathways to amplify apoptotic stress in the context of cancer therapy? Why are respiration and apoptotic regulation housed in the same organelle? Here, we briefly review mitochondrial respiration and apoptosis and then focus on how the intersection of these two processes is regulated by cytoplasmic signaling pathways such as the integrated stress response.

Keywords: CRISPR; apoptosis; cancer; electron transport chain; integrated stress response; leukemia; mitochondria; oncology; oxidative phosphorylation; respiration; stress; venetoclax.

Figure 1:. How mitochondria send and receive stress signals

(A) Overview of a mito-nuclear signaling pathway that communicates mitochondrial dysfunction via the protein messenger DELE1. The protease OMA1 cleaves DELE1 to generate a short fragment (DELE1-S) that migrates to the cytoplasm and allosterically activates the eIF2α, kinase HRI. Phosphorylation of eIF2α, triggers the integrated stress response (ISR), which is a pleiotropic transcriptional program. The ISR inhibits mTORC1 via Sestrin2 and Redd1, leading to activation of autophagy and inhibition of translation. Other effects of the ISR include activation of the pro-apoptotic BH3-only proteins NOXA and BIM and a reduction in levels of the anti-apoptotic factor MCL1, which contribute to the pro-death phase of the ISR. (B) The mTORC1 pathway modulates mitochondrial function in part through the IMM protease YME1L. In cancer, this signaling pathway may serve to preserve anaplerotic capability during nutrient stress. Reciprocal communication is executed by a distinct but related IMM protease, OMA1, and also through AMPK.

Figure 2). Processes throughout the mitochondrion can affect apoptotic priming.

Venetoclax binds and inhibits BCL2, liberating pro-apoptotic factors that trigger the permeabilization of the OMM by BAX/BAK. Loss of function (e.g. genetic knockout) in proteins shown in cyan makes the cell resistant to Venetoclax. Loss of function in proteins shown in red causes the cell to become more sensitive to Venetoclax, and in some cases can reverse established Venetoclax resistance occurring in vivo. BAX* specifies active BAX that is bound to the OMM, as opposed to cytosolic BAX that exists under basal conditions. OPA1 and cristae junctions suppress cytochrome C efflux during MOMP, as indicated by the “X”.

Figure 3:. Intersection of two stress responses secondary to mitochondrial dysfunction.

ETC dysfunction triggers OMA1 activation, which cleaves multiple substrates, including OPA1 and DELE1. Initially this activity serves a pro-homeostatic response. Prolonged stress activates the pro-apoptotic arm of the integrated stress response, which converges on BCL2 family proteins to trigger MOMP. Cleavage of OPA1 and dissolution of cristae junctions may act to internally prime mitochondria to commit to apoptosis in response to MOMP.