Spontaneous activity of the mitochondrial apoptosis pathway drives chromosomal defects, the appearance of micronuclei and cancer metastasis through the Caspase-Activated DNAse

Haimovici, A; Höfer, Christoph; Badr, Mohamed Tarek; Haghighi, Elham Bavafaye; Amer, Tarek; Boerries, Melanie; Bronsert, Peter; Glavynskyi, Ievgen; Fanfone, Deborah; Ichim, Gabriel; Thilmany, Nico; Weber, Arnim; Brummer, Tilman; Spohr, Corinna; Öllinger, Rupert; Janssen, Klaus–Peter; Rad, Roland; Häcker, Georg

doi:10.1038/s41419-022-04768-y

Cited by 21 publications

(15 citation statements)

References 56 publications

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“…It seems however almost inescapable to conclude that this caspase-activation is a result of sub-lethal signalling in the apoptosis pathway. We have recently reported evidence of continuous sub-lethal activity of the mitochondrial apoptosis pathway in human cell lines in culture, where these signals drove growth behaviour of the cells [ 24 ]. Table 1 summarizes these biological functions.…”

Section: Evidence Of Sub-lethal Signals In the Apoptosis Apparatusmentioning

confidence: 99%

“…There is a further facet that has not been sufficiently explored. A regular occurrence during sub-lethal signalling in the apoptosis pathway appears to be the activation of CAD [ 16 , 17 , 19 , 24 , 25 , 89 ]. The DDR that follows the activation of CAD in fact has been the most sensitive marker of sub-lethal signals to date [ 17 , 19 ].…”

Section: Potentially Stimulatory Mitochondrial Componentsmentioning

confidence: 99%

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Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?

Häcker

Haimovici

2022

Cell Death Differ

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One of the tasks of mitochondria is the rule over life and death: when the outer membrane is permeabilized, the release of intermembrane space proteins causes cell death by apoptosis. For a long time, this mitochondrial outer membrane permeabilization (MOMP) has been accepted as the famous step from which no cell returns. Recent results have however shown that this quite plainly does not have to be the case. A cell can also undergo only a little MOMP, and it can efficiently repair damage it has incurred in the process. There is no doubt now that such low-scale permeabilization occurs. A major unclarified issue is the biological relevance. Is small-scale mitochondrial permeabilization an accident, a leakiness of the apoptosis apparatus, perhaps during restructuring of the mitochondrial network? Is it attempted suicide, where cell death by apoptosis is the real goal but the stimulus failed to reach the threshold? Or, more boldly, is there a true biological meaning behind the event of the release of low amounts of mitochondrial components? We will here explore this last possibility, which we believe is on one hand appealing, on the other hand plausible and supported by some evidence. Recent data are consistent with the view that sub-lethal signals in the mitochondrial apoptosis pathway can drive inflammation, the first step of an immune reaction. The apoptosis apparatus is almost notoriously easy to trigger. Sub-lethal signals may be even easier to set off. We suggest that the apoptosis apparatus is used in this way to sound the call when the first human cell is infected by a pathogen.

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Section: Evidence Of Sub-lethal Signals In the Apoptosis Apparatusmentioning

confidence: 99%

Section: Potentially Stimulatory Mitochondrial Componentsmentioning

confidence: 99%

Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?

Häcker

Haimovici

2022

Cell Death Differ

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“…The examination of MN formation in CAMLs in early stage CRC might allow for discriminating more aggressive disease and target these disease subtypes with more aggressive treatment interventions. Further of interest, is identifying which chromosomes are more involved in the formation of MN, and if MN formation is associated with other oncogenic events such as exosome signaling and mitochondrial apoptosis [ 35 , 36 ]. Lastly, the cytosolic DNA has been shown to upregulate certain immune markers such as PD-L1 [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Micronuclei in Circulating Tumor Associated Macrophages Predicts Progression in Advanced Colorectal Cancer

et al. 2022

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Micronuclei (MN) are fragments of damaged nucleic acids which budded from a cell’s nuclei as a repair mechanism for chromosomal instabilities, which within circulating white blood cells (cWBCs) signifies increased cancer risk, and in tumor cells indicates aggressive subtypes. MN form overtime and with therapy induction, which requires sequential monitoring of rarer cell subpopulations. We evaluated the peripheral blood (7.5 mL) for MN in Circulating Stromal Cells (CStCs) in a prospective pilot study of advanced colorectal cancer patients (n = 25), identifying MN by DAPI+ structures (<3 µm) within the cellular cytoplasm. MN+ was compared to genotoxic induction, progression free survival (PFS) or overall survival (OS) hazard ratios (HR) over three years. MN were identified in 44% (n = 11/25) of CStCs, but were not associated with genotoxic therapies (p = 0.110) nor stage (p = 0.137). However, presence of MN in CStCs was independently prognostic for PFS (HR = 17.2, 95% CI 3.6–80.9, p = 0.001) and OS (HR = 70.3, 95% CI 6.6–752.8, p = 0.002), indicating a non-interventional mechanism in their formation. Additionally, MN formation did not appear associated with chemotherapy induction, but was correlated with tumor response. MN formation in colorectal cancer is an underlying biological mechanism that appears independent of chemotherapeutic genotoxins, changes during treatment, and predicts for poor clinical outcomes.

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“…We used Li et al, and Bauer et al, publications to define signatures of ferroptosis and MPT derived necrosis [ 2 , 27 ]. In addition to our local datasets, we used five datasets for HeLa cell lines with gene accession numbers GSE188567, GSE186370, GSE155493, GSE157717, and GSE174116 obtained from gene expression omnibus (GEO) database [ 1 , 10 , 17 ]. Normalized read counts were used for hierarchical clustering and results were visualized in heatmaps format using GenePattern.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms of metabolic stress induced cell death of human oligodendrocytes: relevance for progressive multiple sclerosis

Fernandes,

Mohammadnia,

Pernin

et al. 2023

acta neuropathol commun

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Oligodendrocyte (OL) injury and loss are central features of evolving lesions in multiple sclerosis. Potential causative mechanisms of OL loss include metabolic stress within the lesion microenvironment. Here we use the injury response of primary human OLs (hOLs) to metabolic stress (reduced glucose/nutrients) in vitro to help define the basis for the in situ features of OLs in cases of MS. Under metabolic stress in vitro, we detected reduction in ATP levels per cell that precede changes in survival. Autophagy was initially activated, although ATP levels were not altered by inhibitors (chloroquine) or activators (Torin-1). Prolonged stress resulted in autophagy failure, documented by non-fusion of autophagosomes and lysosomes. Consistent with our in vitro results, we detected higher expression of LC3, a marker of autophagosomes in OLs, in MS lesions compared to controls. Both in vitro and in situ, we observe a reduction in nuclear size of remaining OLs. Prolonged stress resulted in increased ROS and cleavage of spectrin, a target of Ca2+-dependent proteases. Cell death was however not prevented by inhibitors of ferroptosis or MPT-driven necrosis, the regulated cell death (RCD) pathways most likely to be activated by metabolic stress. hOLs have decreased expression of VDAC1, VDAC2, and of genes regulating iron accumulation and cyclophilin. RNA sequencing analyses did not identify activation of these RCD pathways in vitro or in MS cases. We conclude that this distinct response of hOLs, including resistance to RCD, reflects the combined impact of autophagy failure, increased ROS, and calcium influx, resulting in metabolic collapse and degeneration of cellular structural integrity. Defining the basis of OL injury and death provides guidance for development of neuro-protective strategies.

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Spontaneous activity of the mitochondrial apoptosis pathway drives chromosomal defects, the appearance of micronuclei and cancer metastasis through the Caspase-Activated DNAse

Cited by 21 publications

References 56 publications

Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?

Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?

Micronuclei in Circulating Tumor Associated Macrophages Predicts Progression in Advanced Colorectal Cancer

Mechanisms of metabolic stress induced cell death of human oligodendrocytes: relevance for progressive multiple sclerosis

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