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Linking cellular stress responses to systemic homeostasis


Mammalian cells respond to stress by activating mechanisms that support cellular functions and hence maintain microenvironmental and organismal homeostasis. Intracellular responses to stress, their regulation and their pathophysiological implications have been extensively studied. However, little is known about the signals that emanate from stressed cells to enable a coordinated adaptive response across tissues, organs and the whole organism. Considerable evidence has now accumulated indicating that the intracellular mechanisms that are activated in response to different stresses — which include the DNA damage response, the unfolded protein response, mitochondrial stress signalling and autophagy — as well as the mechanisms ensuring the proliferative inactivation or elimination of terminally damaged cells — such as cell senescence and regulated cell death — are all coupled with the generation of signals that elicit microenvironmental and/or systemic responses. These signals, which involve changes in the surface of stressed cells and/or the secretion of soluble factors or microvesicles, generally support systemic homeostasis but can also contribute to maladaptation and disease.

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The authors apologize to the authors of several high-quality articles dealing with the links between intracellular stress responses and the regulation of organismal homeostasis that were not able to be discussed and cited owing to space limitations. L.G. is supported by a start-up grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, NY, USA), by industrial grants from Lytix (Oslo, Norway) and Phosplatin (New York, NY, USA), and by donations from Sotio a.s. (Prague, Czech Republic), the Luke Heller TECPR2 Foundation (Boston, MA, USA) and Phosplatin (New York, NY, USA). G.K. is supported by the Ligue contre le Cancer Comité de Charente-Maritime (Équipe Labellisée); the Agence National de la Recherche (ANR) — Projets Blancs; ANR under the framework of E-Rare-2, the ERA-Net for Research on Rare Diseases; the Association pour la Recherche sur le Cancer (ARC); Cancéropôle Ile-de-France; Chancelerie des Universités de Paris (Legs Poix), the Fondation pour la Recherche Médicale (FRM); a donation by Elior; the European Commission (ArtForce); the European Research Council (ERC); the Fondation Carrefour; the Institut National du Cancer (INCa); INSERM (HTE); the Institut Universitaire de France; the LeDucq Foundation; the LabEx Immuno-Oncology; RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM). L.G.’s homepage: G.K.’s homepage:

Reviewer information

Nature Reviews Molecular Cell Biology thanks C. Hetz, B. Schumacher and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

All authors researched data for the article, wrote the article and edited the manuscript. L.G. and G.K. contributed to discussion of the content before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Lorenzo Galluzzi or Guido Kroemer.


Pattern recognition receptors

Evolutionarily conserved receptors that elicit inflammation and innate immunity upon recognition of conserved microbial products or endogenous danger signals.

Regulated cell death

(RCD). Variant of cell death that relies on a dedicated, genetically encoded machinery and hence can be delayed or accelerated with pharmacological or genetic interventions.

Cell cycle checkpoints

Control mechanisms that ensure the progression of eukaryotic cells along the cell cycle only in the presence of favourable conditions.


The ability to trigger an immune response, resulting from antigenicity (the property of being recognized by immune cells) and adjuvanticity (the property of delivering activating signals to immune cells).

Natural killer (NK) cells

A group of cells from the innate lymphoid immune system that can mediate cytotoxic functions independent of antigen recognition.

Major histocompatibility complex

(MHC). Set of cell surface proteins essential for the immune system to recognize foreign molecules in vertebrates.

Abscopal responses

Measurable reductions in the size of a non-irradiated tumour or metastasis thereof following the irradiation of another lesion.

Hypofractionated irradiation

The delivery of radiation therapy in a few fractions, each with a larger dose than the standard 1.8 or 2 Gy.


Small enveloped structures that encompass chromosomes of fragments thereof that are not incorporated into one of the daughter nuclei during mitosis.


A process whereby up to thousands of clustered chromosomal rearrangements occur in a single event in localized genomic regions affecting one or a few chromosomes.


The maintenance of protein homeostasis within a defined organelle, cell or tissue, which involves correct protein synthesis, folding, distribution and degradation.


One of several small proteins or proteoglycans that are released by myocytes upon contraction to mediate autocrine, paracrine or endocrine effects.

Nuclear factor-κB (NF-κB) signalling

Biological output of NF-κB-dependent transcription, generally involving a robust pro-inflammatory component.

Hepcidin antimicrobial peptide

(HAMP). Key negative regulator of circulating iron availability in mammals, promoting a state of accrued bacterial resistance.

Brown adipose tissue

Highly specialized adipose tissue, the main function of which is to produce heat (thermogenesis).

Dendritic cells

Myeloid cells that play a major role in the initiation of T cell-dependent immune responses.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of cells that are defined by their myeloid origin, immature state and ability to potently suppress T cell responses.

Integrated stress response

Evolutionarily conserved homeostatic programme common to all eukaryotic cells.


Soluble factors released by cells experiencing mitochondrial stress and operating as autocrine, paracrine or endocrine mediators.

AMP-activated protein kinase

(AMPK). Phylogenetically conserved enzyme expressed by all mammalian cells that has a major role in the regulation of energy metabolism.

Mitochondrial outer membrane permeabilization

(MOMP). Loss of integrity of the outer mitochondrial membrane that generally precipitates regulated cell death through apoptosis.


Supramolecular complex responsible for the caspase 1-dependent maturation of IL-1β and IL-18 in response to microbial products or other danger signals.

γδ T lymphocytes

T cells expressing a γδ (rather than an αβ) T cell receptor, which is associated with a fairly limited antigenic repertoire but major histocompatibility complex-independent recognition.

Cancer-associated fibroblasts

Fibroblasts that are found in the tumour microenvironment and generally support malignant cells by nutritional and immunological mechanisms.

Ketone bodies

Three related compounds (acetone, acetoacetic acid and β-hydroxybutyric acid) that are produced during the metabolism of lipids.

Stellate cells

Hepatic or pancreatic cells that have a major role in the establishment and maintenance of fibrosis.

Pro-opiomelanocortin neurons

Hypothalamic neurons capable of synthesizing pro-opiomelanocortin (POMC), the precursor of circulating melanocyte stimulating hormone, adrenocorticotropin hormone and β-endorphin

Non-conventional secretion

Process through which intracellular proteins and other cytoplasmic components are released into the extracellular milieu independently of the endoplasmic reticulum and Golgi apparatus.

Paneth cells

Cells from the intestinal epithelium that contribute to the maintenance of the gastrointestinal barrier.

Crohn’s disease

Chronic inflammatory condition of the gastrointestinal tract associated with an increased risk of colorectal cancer.


Cell-derived small vesicles that are present in virtually all mammalian fluids, including blood and urine.

Senolytic drugs

Agents that selectively kill senescent cells.

Programmed cell death

(PCD). Purely physiological variant of regulated cell death that contributes to post-embryonic or embryonic development as well as to the maintenance of adult tissue homeostasis.

Systemic lupus erythematosus

(SLE). Mild to severe autoimmune disease affecting a variety of tissues, including joints, skin, heart and lungs.

LC3-associated phagocytosis

Specific variant of the phagocytic process that relies on multiple, but not all, components of the molecular apparatus for autophagy.

Damage-associated molecular patterns

(DAMPs). Endogenous molecules that, upon exposure on the plasma membrane or secretion, can be recognized by a pattern recognition receptor and hence participate in the regulation of inflammatory responses.


Variant of regulated cell death that is associated with the formation of pores in the plasma membrane by one of multiple gasdermin family members.

RIGI-like receptors

(RLRs). Intracellular pattern recognition receptors involved in the recognition of nucleic acids (generally, but not exclusively, of viral origin).


Variant of regulated cell death that involves RIPK3-dependent activation of MLKL, resulting in plasma membrane permeabilization.

Immunogenic cell death

(ICD). Functionally defined variant of regulated cell death that is sufficient (in immunocompetent hosts) to establish protective immune responses specific for antigens from dying cells.

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Fig. 1: Integration of cellular and systemic stress responses and their roles in the maintenance of organismal homeostasis.
Fig. 2: The DDR and UPRER in the regulation of microenvironmental and systemic homeostasis.
Fig. 3: Mitochondrial stress responses and autophagy in the regulation of microenvironmental and systemic homeostasis.
Fig. 4: Cellular senescence and RCD in the regulation of microenvironmental and systemic homeostasis.