Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage

Cao, Kai; Riley, Joel S.; Heilig, Rosalie; Montes-Gómez, Alfredo E; Vringer, Esmee; Berthenet, Kevin; Cloix, Catherine; Elmasry, Yassmin; Spiller, David G.; Ichim, Gabriel; Campbell, Kirsteen J.; Gilmore, Andrew; Tait, Stephen W.G.

doi:10.1016/j.devcel.2022.03.019

Cited by 53 publications

(28 citation statements)

References 58 publications

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“…Of note, although MOMP was initially conceived as an ‘all-or-nothing’ phenomenon that would necessarily result in cell death 45 , sublethal instances of MOMP that affect only a fraction of the mitochondrial pool and do not engage RCD — known as ‘minority MOMP’ — have been described in various physiological and pathological settings 49 , 50 . In the context of sublethal stress conditions, minority MOMP, which is actively prevented by mitochondrial fusion as a consequence of BCL-2 redistribution 51 , not only enables inflammatory reactions driven by mtDAMPs 52 , 53 but also favours DNA damage upon activation of DNA fragmentation factor subunit-β (DFFB) 49 , which can further activate inflammatory pathways.…”

Section: Mtdamp Signalling Pathwaysmentioning

confidence: 99%

Mitochondrial control of inflammation

et al. 2022

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Numerous mitochondrial constituents and metabolic products can function as damage-associated molecular patterns (DAMPs) and promote inflammation when released into the cytosol or extracellular milieu. Several safeguards are normally in place to prevent mitochondria from eliciting detrimental inflammatory reactions, including the autophagic disposal of permeabilized mitochondria. However, when the homeostatic capacity of such systems is exceeded or when such systems are defective, inflammatory reactions elicited by mitochondria can become pathogenic and contribute to the aetiology of human disorders linked to autoreactivity. In addition, inefficient inflammatory pathways induced by mitochondrial DAMPs can be pathogenic as they enable the establishment or progression of infectious and neoplastic disorders. Here we discuss the molecular mechanisms through which mitochondria control inflammatory responses, the cellular pathways that are in place to control mitochondria-driven inflammation and the pathological consequences of dysregulated inflammatory reactions elicited by mitochondrial DAMPs.

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Section: Mtdamp Signalling Pathwaysmentioning

confidence: 99%

Mitochondrial control of inflammation

et al. 2022

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“…Mitochondria normally form a network that is constantly changing by fission and fusion: small parts of the tubular network bud off and form ‘individual’ mitochondria (fission), but portions of the network can also join by fusion. The first possibility of permeabilization is that individual mitochondria are completely permeabilized and empty their entire contents [ 18 ]. The second possibility is that larger parts of the network release limited pools of activating molecules.…”

Section: What Is Happening At Mitochondria When the Apoptosis Apparat...mentioning

confidence: 99%

“…This difference is meaningful. Complete permeabilization may release all mitochondrial contents, including matrix molecules such as mtDNA and RNA [ 18 ]. Incomplete permeabilization is probably limited to the release of intermembrane space proteins such as cytochrome c and Smac (Fig.…”

Section: What Is Happening At Mitochondria When the Apoptosis Apparat...mentioning

confidence: 99%

“…Small-scale, sub-lethal signalling of the apoptosis apparatus has been described originating from the TRAIL death receptor [ 16 ] and from signals of the mitochondrial apoptosis pathway [ 17 ]. During mitochondrial apoptosis, the whole network of mitochondria undergoes MOMP, but there is the possibility of only a few individual mitochondria, which appear to have fissioned off the network, to permeabilize and to release cytochrome c [ 17 , 18 ]. The term ‘minority MOMP’ has been coined to describe this event [ 17 ].…”

Section: Introductionmentioning

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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“…Finally, our observations regarding increased fragmentation and permeabilization of mitochondria in ER-xl axons are reminiscent of miMOMP and subsequent sublethal caspase-3 activation as recently described in cancer cells. 50 Indeed, in ER-xl axons, mitochondria might be similarly primed to death, promoting caspase-3 activation with consequences on axon arborescence and synaptogenesis.…”

Section: Discussionmentioning

confidence: 99%