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Mitochondria as multifaceted regulators of cell death

Abstract

Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential across different diseases, including neurodegenerative diseases, autoimmune disorders and cancer. In this Review, we discuss new insights into how mitochondria regulate apoptotic cell death. Surprisingly, recent data demonstrate that besides eliciting caspase activation, MOMP engages various pro-inflammatory signalling functions. As we highlight, together with new findings demonstrating cell survival following MOMP, this pro-inflammatory role suggests that mitochondria-derived signalling downstream of pro-apoptotic cues may also have non-lethal functions. Finally, we discuss the importance and roles of mitochondria in other forms of regulated cell death, including necroptosis, ferroptosis and pyroptosis. Collectively, these new findings offer exciting, unexplored opportunities to target mitochondrial regulation of cell death for clinical benefit.

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Fig. 1: Apoptotic signalling pathways.
Fig. 2: BAX/BAK-mediated mitochondrial outer membrane permeabilization.
Fig. 3: Differential levels of mitochondrial outer membrane permeabilization permit cell survival and unmask signalling functions.
Fig. 4: Pro-inflammatory effects of mitochondrial outer membrane permeabilization.
Fig. 5: Inhibition of mitochondrial outer membrane permeabilization-induced inflammation.
Fig. 6: Mitochondria and non-apoptotic cell death.
Fig. 7: Strategies to target mitochondrial apoptosis in disease.

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Acknowledgements

The authors thank S. Dixon and T. Mouldoveanu for discussion and critical input. Research in the authors’ laboratory is supported by funding from Cancer Research UK (C40872/A20145) and Prostate Cancer UK (RIA17-ST2-002).

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Correspondence to Stephen W. G. Tait.

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Glossary

BH3-mimetics

Drugs modelled after the pro-apoptotic BH3 domain of BH3-only proteins that are used in cancer therapy.

Death-inducing signalling complex

(DISC). A complex consisting of death receptor, Fas-associated death domain (FADD) and caspase 8 that can mediate apoptosis.

SMAC

(Also known as DIABLO). A mitochondrial intermembrane space protein that upon mitochondrial outer membrane permeabilization binds to and inhibits XIAP.

OMI

(Also known as HtrA2). A serine protease located within the mitochondrial intermembrane space that binds to and inhibits XIAP following mitochondrial outer membrane permeabilization.

XIAP

A protein that binds to and inhibits caspases 3, 7 and 9.

Endoplasmic reticulum-associated degradation

Pathway that serves to degrade misfolded endoplasmic reticulum (ER) proteins by the proteasome, mitigating ER stress.

Neoantigens

Newly generated antigens that, in cancer, usually arise from mutated genes.

Type I interferon

Class of cytokines mediating inflammation.

SMAC-mimetic compounds

Chemicals that were designed to phenocopy the inhibitor of apoptosis protein-binding and inhibitory properties of SMAC.

NLRP3 inflammasome

A protein complex containing NOD-, LRR- and pyrin domain-containing 3 (NLRP3) and caspase 1 that processes and activates inflammatory cytokines such as IL-1β and IL-18.

RNA degradasome

A multiprotein complex present in bacteria and mitochondria that degrades RNA.

‘Find-me’ and ‘eat-me’ signals

Molecular signals used by dying cells to attract phagocytes; examples of find-me signals include ATP and lysophosphatidylcholine, and the best-characterized eat-me signal is phosphatidylserine.

Ischaemic injury

Hypoxia-mediated injury due to diminished blood flow.

Toll receptor

A class of protein receptors that serve a key role in innate immunity by sensing conserved molecules derived from microorganisms.

Necrosome

A protein complex containing receptor interacting protein kinase 1 (RIPK1) and RIPK3 that promotes necroptotic cell death.

Fenton reaction

The reaction of peroxides with iron to yield free radicals.

Glutathione

A key cellular antioxidant that scavenges reactive oxygen species through reduction.

Ferritin

An iron-binding protein that plays important roles in the storage and transport of iron throughout the body.

Haeme

An iron-containing coordination complex present in haemoproteins such as haemoglobin, catalases and cytochrome c.

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Bock, F.J., Tait, S.W.G. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol 21, 85–100 (2020). https://doi.org/10.1038/s41580-019-0173-8

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