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

Häcker, Georg; Haimovici, A

doi:10.1038/s41418-022-01058-0

Cited by 19 publications

(14 citation statements)

References 99 publications

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“…We focused on the intrinsic pathway of apoptosis, by which cell death normally occurs in response to persistent intracellular stresses. [69][70][71] Consistent with the relatively muted signaling of this pathway relative to, for example, pyroptosis, we found that the apoptosome lacks supersaturable DFDs (Figure S5A).…”

Section: Supersaturation Drives Signal Amplification In Human Cellssupporting

confidence: 69%

Protein supersaturation powers innate immune signaling

Gama

Miller

Lange

et al. 2023

Preprint

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The response of cells to existential threats such as virus invasion often involves semi-crystalline polymerization of certain signaling proteins, but the highly ordered nature of the polymers has no known function. We hypothesized that the undiscovered function is kinetic in nature, emerging from the nucleation barrier to the underlying phase transition, rather than the material polymers themselves. We explored this idea using fluorescence microscopy and Distributed Amphifluoric FRET (DAmFRET) to characterize the phase behavior of all 116 members of the death fold domain (DFD) superfamily, the largest group of putative polymer modules in human immune signaling. A subset of them polymerized in a nucleation-limited manner able to digitize cell state. These were enriched for the highly connected hubs of the DFD protein-protein interaction network. Full-length (F.L) signalosome adaptors retained this activity. We then designed and carried out a comprehensive nucleating interaction screen to map the pathways of signaling through the network. The results recapitulated known signaling pathways including a recently discovered link between the different cell death subroutines of pyroptosis and extrinsic apoptosis. We went on to validate this nucleating interaction in vivo. In the process, we discovered that the inflammasome is powered by constitutive supersaturation of the adaptor protein, ASC, implying that innate immune cells are thermodynamically fated for inflammatory cell death. Finally, we showed that supersaturation in the extrinsic apoptosis pathway commits cells to die, whereas the lack of supersaturation in the intrinsic apoptosis pathway permits cells to recover. Our results collectively suggest that innate immunity comes at the cost of occasional spontaneous cell death, and uncover a physical basis for the progressive nature of age-associated inflammation.

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Section: Supersaturation Drives Signal Amplification In Human Cellssupporting

confidence: 69%

Protein supersaturation powers innate immune signaling

Gama

Miller

Lange

et al. 2023

Preprint

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show abstract

“…Many proinflammatory pathways occur during mitochondrial outer membrane permeabilization, a critical factor in cell death during mitochondrial apoptosis. Recent studies are consistent with sublethal signaling in the mitochondrial apoptotic pathway driving inflammation, the first step in the immune response [112] …”

Section: Inflammation Dna Damage and Mitochondrial Imbalancesupporting

confidence: 59%

“…Recent studies are consistent with sublethal signaling in the mitochondrial apoptotic pathway driving inflammation, the first step in the immune response. [112] Infiltrated mitochondria trigger inflammation partly by releasing mitochondria-derived damage-associated molecular patterns (DAMPs). As DAMPs, histones are a class of endogenous molecules that trigger the immune response by directly interacting with the cell membrane and activating pattern recognition receptors.…”

Section: Inflammation Dna Damage and Mitochondrial Imbalancementioning

confidence: 99%

Understanding the role of inflammation in sensorineural hearing loss: Current goals and future prospects

Li,

Chen,

Lin

et al. 2023

Brain-X

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Sensorineural hearing loss (SNHL) is a common otologic condition caused by damage to hair cells and spiral ganglion neurons that affects transmission pathways. Most of these cells cannot be regenerated, and there has been no breakthrough in regeneration techniques for inner ear cells. SNHL has a high incidence rate and can cause a variety of clinical symptoms, greatly impacting people's daily lives. With limited clinical treatments, the search for critical targets is urgent. Studies have shown that inflammation is prevalent in the pathogenesis of SNHL and plays a significant role in it. Inflammation is a normal body defense response, and a systemic anti‐inflammatory approach is undesirable. It is crucial for us to identify potential targets of inflammation in SNHL and take measures specifically targeting those targets with minimal systemic impact. This paper firstly describes the role of inflammation in various types of SNHL and then provides an overview of the interactions between inflammation and cochlear immunity, cochlear microcirculation, vascular spasm, and glutamate metabolism and finally comprehensively examines the feasibility of targets in these interactions. This paper is expected to facilitate the development of targeted anti‐inflammation for SNHL and provide strategies and approaches for treating clinical SNHL.

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“…IAPs are also crucial regulators of inflammatory pathways because they influence both the activation of inflammatory genes and the induction of cell death through the receptorinteracting serine-threonine protein kinases (RIPKs), nuclear factor κB (NF-κB)-inducing kinase, and mitogen-activated protein kinases (MAPKs). Several studies have revealed an anti-inflammatory potential of RIPK inhibitors that either block inflammatory signaling or block the form of inflammatory cell death known as necroptosis [37,38]. There are several endogenous inhibitors of death that protect cells from programmed death.…”

Section: Apoptosis-mitochondria Interactionmentioning

confidence: 99%

Is death a living being?

Abdelrazak Mansour Ali,

Radwa Abdelrazak Ali,

Ahmed Abdelrazak Ali

2023

Int. J. Sci. Technol. Res. Arch

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The death process begins with the loss of function of one or more of the three classic vital organs: the heart, the brain, and/or the lungs. Failure to resuscitate the function of the affected primary organ leads to the cessation of the function of other organs. The cell carries death factors or elements such as caspases and some mitochondrial secretions - At the same time the mitochondria represent the basic source of energy and life in the cell. Death occurs only when activating the molecules and factors of cell annihilation. Apoptosis is a type of cell death mechanism, controlled by interactions between several molecules - and is responsible for removing unwanted cells from the body. Apoptosis can be induced by signals from inside the cell or by death signals coming from outside the cell via cosmic energy waves. Caspases are cysteine aspartate-specific proteases that are essential for the initiation and execution of apoptosis. As one of the initiator and executor caspases, caspase-2 is the most evolutionally conserved caspase, exerting both apoptotic and non-apoptotic functions. Caspases also have a role in inflammation, whereby they directly process proinflammatory cytokines such as pro-IL1β. These are signaling molecules that allow recruitment of immune cells to an infected cell or tissue. In addition to apoptosis, caspases play a role in necroptosis, pyroptosis, and autophagy, which are non-apoptotic cell death processes. Mitochondria coordinate cell stress responses, such as autophagy, and control nonapoptotic cell death routines, such as regulated necrosis. Mitochondrial permeabilization leads to release of these proteins, which then interfere with the IAP-inhibition of caspases, resulting in potentiation of cell death. Initiators of mitochondrial-driven inflammation include the release of mitochondrial dsRNA and mt DNA thereby initiating type I interferons. It is concluded that mitochondria not only power the metabolic cell activities with energy but also power the cell death with both energy and signaling molecules denoting that cell death is an active living being.

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

Cited by 19 publications

References 99 publications

Protein supersaturation powers innate immune signaling

Protein supersaturation powers innate immune signaling

Understanding the role of inflammation in sensorineural hearing loss: Current goals and future prospects

Is death a living being?

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