Mitochondria in Cell Senescence: Is Mitophagy the Weakest Link? - PubMed (original) (raw)

Review

Viktor I Korolchuk et al. EBioMedicine. 2017 Jul.

Abstract

Cell senescence is increasingly recognized as a major contributor to the loss of health and fitness associated with aging. Senescent cells accumulate dysfunctional mitochondria; oxidative phosphorylation efficiency is decreased and reactive oxygen species production is increased. In this review we will discuss how the turnover of mitochondria (a term referred to as mitophagy) is perturbed in senescence contributing to mitochondrial accumulation and Senescence-Associated Mitochondrial Dysfunction (SAMD). We will further explore the subsequent cellular consequences; in particular SAMD appears to be necessary for at least part of the specific Senescence-Associated Secretory Phenotype (SASP) and may be responsible for tissue-level metabolic dysfunction that is associated with aging and obesity. Understanding the complex interplay between these major senescence-associated phenotypes will help to select and improve interventions that prolong healthy life in humans.

Search strategy and selection criteria: Data for this review were identified by searches of MEDLINE, PubMed, and references from relevant articles using the search terms "mitochondria AND senescence", "(autophagy OR mitophagy) AND senescence", "mitophagy AND aging" and related terms. Additionally, searches were performed based on investigator names. Abstracts and reports from meetings were excluded. Articles published in English between 1995 and 2017 were included. Articles were selected according to their relevance to the topic as perceived by the authors.

Keywords: Aging; Mitochondria; Mitophagy; Senescence.

Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

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Figures

Fig. 1

Fig. 1

Senescence drives changes in cell bioenergetics. Human MRC5 fibroblasts were either fully proliferation competent (young) or replicatively senescent (sen). Cellular oxygen consumption rates and extracellular acidification rates were assayed in medium containing 5 mM glucose, 2 mM

l

-glutamate and 3% FBS using a Seahorse XF24 analyzer. A) Oxygen consumption rates showing basal condition, and after sequential additions of the following drugs as indicated: oligomycin (to block ATP synthesis), the uncoupler FCCP (to stimulate respiration) and Antimycin A (to block the electron transport chain at complex III). B) Relative glycolytic and mitochondrial ATP production rates were calculated using the data generated in Fig. 1A as described (Mookerjee and Brand, 2015). Data are mean ± SD from 20 samples from 2 independent experiments.

Fig. 2

Fig. 2

The potential role of mitophagy in senescence. A) Diagram showing the process of autophagy, exemplified by mitophagy. Cytoplasmic contents including organelles such as mitochondria are sequestered into double-membraned phagophore structures. This process can be selective and involves a number of receptor proteins; specifically for mitochondria these include NDP52, optineurin and TAXBP1. These receptor proteins bind to poly-ubiquitinated proteins which, via binding to the phagophore-resident protein LC3, recruit their cargo to the growing autophagosome. Ubiquitination of mitochondrial surface proteins can occur via stabilisation of PINK1 (PTEN-induced kinase 1) on the mitochondrial surface, which recruits the E3 ubiquitin ligase, Parkin to mitochondrial membranes, thus promoting the ubiquitination and clearance of damaged mitochondria. The fully enclosed autophagosome is trafficked to and fuses with lysosomes. The contents of the subsequent autolysosome are degraded by lysosomal enzymes including hydrolases and proteases. mTORC1 integrates intra- and extra-cellular signals and drives cell growth as well as inhibiting autophagy. B) In young proliferating cells, mTORC1 carefully balances anabolic vs catabolic metabolism in response to the cellular environment. Both mTORC1 activity and autophagy are elevated in senescent cells while the specific process of mitophagy is reduced (see text for more details). Autophagy has a complex relationship with senescence and can both promote and inhibit senescence and senescence-associated phenotypes. For example in the context of OIS, autophagy induction can either promote or suppress acquisition of senescence while the specific role of mitophagy in OIS is currently less clear. Conversely, lifespan-extending interventions such as caloric restriction and rapamycin induce autophagy and mitophagy and relieve senescence-associated phenotypes.

Fig. 3

Fig. 3

The cell senescence signalling network. Signals downstream of the DDR cause mitochondrial dysfunction via p38MAPK and TGFβ, SASP and chronic inflammation via NF-κB and C/EBPβ and may directly or indirectly suppress autophagy and mitophagy. SASP and mitochondrial dysfunction feedback to maintain and enhance DNA damage at least partly via ROS generation. Many potential interactions within the network (indicated by red arrows) are still insufficiently understood. See text for further details.

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