Cellular senescence links mitochondria-ER contacts and aging

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Abstract

Membrane contact sites emerged in the last decade as key players in the integration, regulation and transmission of many signals within cells, with critical impact in multiple pathophysiological contexts. Numerous studies accordingly point to a role for mitochondria-endoplasmic reticulum contacts (MERCs) in modulating aging. Nonetheless, the driving cellular mechanisms behind this role remain unclear. Recent evidence unravelled that MERCs regulate cellular senescence, a state of permanent proliferation arrest associated with a pro-inflammatory secretome, which could mediate MERC impact on aging. Here we discuss this idea in light of recent advances supporting an interplay between MERCs, cellular senescence and aging.

Abstract

This perspective by Ziegler et al. explores the impact of mitochondria-endoplasmic reticulum contacts (MERCs) biology on cellular senescence. The authors also explore the potential impacts of MERCs perturbation and how this relates to the increase in cellular senescence observed in common age-related diseases.

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A role for mitochondria in NLRP3 inflammasome activation.

Rongbin Zhou, Amir Yazdi, Philippe Menu … (2011)

An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.

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Cellular Senescence: Defining a Path Forward

Vassilis G. Gorgoulis, Peter Adams, Andrea Alimonti … (2019)

Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.

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Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.

Darren J. Baker, Tobias Wijshake, Tamar Tchkonia … (2012)

Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.

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Author and article information

Contributors

Dorian V. Ziegler: dorian.ziegler@unil.ch

Nadine Martin:

ORCID: http://orcid.org/0000-0002-4806-2388

nadine.martin@lyon.unicancer.fr

David Bernard:

ORCID: http://orcid.org/0000-0002-1557-2074

david.bernard@lyon.unicancer.fr

Journal

Journal ID (nlm-ta): Commun Biol

Journal ID (iso-abbrev): Commun Biol

Title: Communications Biology

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2399-3642

Publication date (Electronic): 24 November 2021

Publication date PMC-release: 24 November 2021

Publication date Collection: 2021

Volume: 4

Electronic Location Identifier: 1323

Affiliations

[1 ]GRID grid.462282.8, ISNI 0000 0004 0384 0005, Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, , Université de Lyon, Centre Léon Bérard, ; Lyon, France

[2 ]GRID grid.9851.5, ISNI 0000 0001 2165 4204, Center for Integrative Genomics, , University of Lausanne, ; Lausanne, Switzerland

Author information

Nadine Martin http://orcid.org/0000-0002-4806-2388

David Bernard http://orcid.org/0000-0002-1557-2074

Article

Publisher ID: 2840

DOI: 10.1038/s42003-021-02840-5

PMC ID: 8613202

PubMed ID: 34819602

SO-VID: 3bff80d7-8254-4834-b2a4-ccdb6e2e90c7

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 23 July 2021

Date accepted : 30 October 2021

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Keywords: senescence,pathogenesis

Data availability:

Keywords: senescence, pathogenesis

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Cellular senescence links mitochondria-ER contacts and aging

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Most cited references 163

A role for mitochondria in NLRP3 inflammasome activation.

Cellular Senescence: Defining a Path Forward

Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.

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