A non‐death function of the mitochondrial apoptosis apparatus in immunity

http://emboj.embopress.org/content/early/2019/04/12/embj.2018100907

Dominik Brokatzky, Benedikt Dörflinger, Aladin Haimovici, Arnim Weber, Susanne Kirschnek, Juliane Vier, Arlena Metz, Julia Henschel, Tobias Steinfeldt, Ian E. Gentle and Georg Häcke

INTRODUCTION
Apoptosis mostly proceeds through mitochondria: the outer mitochondrial membrane is permeabilized, in a process called mitochondrial outer membrane permeabilization (MOMP). This releases cytochrome c to activate cytosolic caspases, which execute apoptosis through proteolysis of numerous substrates.

Recently, it has been observed that apoptosis signaling may be initiated at a low level, in the absence of cell death. Only few mitochondria are permeabilized, and small amounts of cytochrome c are released, causing only limited caspase activation. Apoptosis appears to be triggered but then aborted before the point of no return. The process has been termed minority MOMP and the cell stays alive and can presumably repair any damage caused

MAIN FACTS OF THE PAPER
The author hypothesise that low-level (sub-lethal) “apoptosis” signaling (minority MOMP) can trigger cytokine secretion, causing inflammation and immune alert. Full apoptosis activates caspases that counteract this immune function. The small amounts of caspase activated during sub-lethal signaling following minority MOMP may however be too low to turn the signal off, resulting in cytokine secretion and immune activation.

Infecting HeLa cells by several agents, they tested this possibility and reported that human cells can react to low-level apoptosis induction with cytokine secretion. Minority MOMP was detected with all infectious agents tested. This suggests that minority MOMP is a very common occurrence during infection. In addition, the authors show that the ability of epithelial cells to fight the growth of parasites is decreased when proapoptotic signaling is deleted.


CONCLUSIONS
Their results suggest that mitochondria have a function in the detection of microbial infection and cell-autonomous immunity, through a sub-lethal (low-intensity) activation of the mitochondrial apoptosis apparatus.

They also report damage to the genomic DNA caused by the mitochondrial apoptosis signaling. Since MOMP seems like a frequent occurrence, this suggests that infection-associated damage to the genomic DNA is widespread. Therefore, this study also identifies DNA damage as a common occurrence during infection and indicate the possibility that infection-associated mutations, potentially leading to cancer, may be a side effect of this system of microbial detection.