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      Mitochondria and aging: A role for the mitochondrial transition pore?

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          Summary

          The cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species ( ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore ( mPTP) in normal aging and in aging‐associated diseases.

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          The role of mitochondria in aging.

          Ana Bratic, Nils-Göran Larsson (2013)
          Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging. Somatic mitochondrial DNA (mtDNA) mutations and respiratory chain dysfunction accompany normal aging, but the first direct experimental evidence that increased mtDNA mutation levels contribute to progeroid phenotypes came from the mtDNA mutator mouse. Recent evidence suggests that increases in aging-associated mtDNA mutations are not caused by damage accumulation, but rather are due to clonal expansion of mtDNA replication errors that occur during development. Here we discuss the caveats of the traditional mitochondrial free radical theory of aging and highlight other possible mechanisms, including insulin/IGF-1 signaling (IIS) and the target of rapamycin pathways, that underlie the central role of mitochondria in the aging process.
          Article 0 comments Cited 400 times – based on 0 reviews     Review now
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            The sites and topology of mitochondrial superoxide production.

            Martin D Brand (2010)
            Mitochondrial superoxide production is an important source of reactive oxygen species in cells, and may cause or contribute to ageing and the diseases of ageing. Seven major sites of superoxide production in mammalian mitochondria are known and widely accepted. In descending order of maximum capacity they are the ubiquinone-binding sites in complex I (site IQ) and complex III (site IIIQo), glycerol 3-phosphate dehydrogenase, the flavin in complex I (site IF), the electron transferring flavoprotein:Q oxidoreductase (ETFQOR) of fatty acid beta-oxidation, and pyruvate and 2-oxoglutarate dehydrogenases. None of these sites is fully characterized and for some we only have sketchy information. The topology of the sites is important because it determines whether or not a site will produce superoxide in the mitochondrial matrix and be able to damage mitochondrial DNA. All sites produce superoxide in the matrix; site IIIQo and glycerol 3-phosphate dehydrogenase also produce superoxide to the intermembrane space. The relative contribution of each site to mitochondrial reactive oxygen species generation in the absence of electron transport inhibitors is unknown in isolated mitochondria, in cells or in vivo, and may vary considerably with species, tissue, substrate, energy demand and oxygen tension. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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              The mitochondrial permeability transition pore and its role in cell death.

              M Crompton (1999)
              This article reviews the involvement of the mitochondrial permeability transition pore in necrotic and apoptotic cell death. The pore is formed from a complex of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocase and cyclophilin-D (CyP-D) at contact sites between the mitochondrial outer and inner membranes. In vitro, under pseudopathological conditions of oxidative stress, relatively high Ca2+ and low ATP, the complex flickers into an open-pore state allowing free diffusion of low-Mr solutes across the inner membrane. These conditions correspond to those that unfold during tissue ischaemia and reperfusion, suggesting that pore opening may be an important factor in the pathogenesis of necrotic cell death following ischaemia/reperfusion. Evidence that the pore does open during ischaemia/reperfusion is discussed. There are also strong indications that the VDAC-adenine nucleotide translocase-CyP-D complex can recruit a number of other proteins, including Bax, and that the complex is utilized in some capacity during apoptosis. The apoptotic pathway is amplified by the release of apoptogenic proteins from the mitochondrial intermembrane space, including cytochrome c, apoptosis-inducing factor and some procaspases. Current evidence that the pore complex is involved in outer-membrane rupture and release of these proteins during programmed cell death is reviewed, along with indications that transient pore opening may provoke 'accidental' apoptosis.
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                Author and article information

                Contributors
                Didier Morin: didier.morin@inserm.fr
                Journal
                Journal ID (nlm-ta): Aging Cell
                Journal ID (iso-abbrev): Aging Cell
                Journal ID (doi): 10.1111/(ISSN)1474-9726
                Journal ID (publisher-id): ACEL
                Title: Aging Cell
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1474-9718
                ISSN (Electronic): 1474-9726
                Publication date (Electronic): 11 June 2018
                Publication date (Print): August 2018
                Volume: 17
                Issue: 4 ( doiID: 10.1111/acel.2018.17.issue-4 )
                Electronic Location Identifier: e12793
                Affiliations
                [ 1 ] INSERM U955, équipe 3 Créteil France
                [ 2 ] Université Paris‐Est, UMR_S955, DHU A‐TVB, UPEC Créteil France
                Author notes
                [*] [* ] Correspondence

                Didier Morin, INSERM U955 – équipe 3, Faculté de Médecine de Créteil, 8, rue Général Sarrail, 94010 Creteil Cedex, France.

                Email: didier.morin@ 123456inserm.fr

                Article
                Publisher ID: ACEL12793
                DOI: 10.1111/acel.12793
                PMC ID: 6052406
                PubMed ID: 29888494
                SO-VID: ff5d71e5-cc39-4954-9be5-994d191e7d9c
                Copyright © © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date accepted : 15 May 2018
                Page count
                Figures: 2, Tables: 0, Pages: 15, Words: 14664
                Funding
                Funded by: Ministère de l'Enseignement Supérieur et de la Recherche
                Award ID: 2014‐140
                Categories
                Subject: Review
                Subject: Reviews
                Custom metadata
                source-schema-version-number 2.0
                component-id acel12793
                cover-date August 2018
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.3 mode:remove_FC converted:19.07.2018

                ScienceOpen disciplines: Cell biology
                Keywords: age‐associated diseases,aging,calcium,mitochondria,mptp,oxidative stress
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: age‐associated diseases, aging, calcium, mitochondria, mptp, oxidative stress

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