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      Mammalian mitophagy – from in vitro molecules to in vivo models

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          Abstract

          The autophagic turnover of mitochondria, termed mitophagy, is thought to play an essential role in not only maintaining the health of the mitochondrial network but also that of the cell and organism as a whole. We have come a long way in identifying the molecular components required for mitophagy through extensive in vitro work and cell line characterisation, yet the physiological significance and context of these pathways remain largely unexplored. This is highlighted by the recent development of new mouse models that have revealed a striking level of variation in mitophagy, even under normal conditions. Here, we focus on programmed mitophagy and summarise our current understanding of why, how and where this takes place in mammals.

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          Most cited references69

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          Autophagy maintains stemness by preventing senescence.

          During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.
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            Nix is a selective autophagy receptor for mitochondrial clearance.

            Autophagy is the cellular homeostatic pathway that delivers large cytosolic materials for degradation in the lysosome. Recent evidence indicates that autophagy mediates selective removal of protein aggregates, organelles and microbes in cells. Yet, the specificity in targeting a particular substrate to the autophagy pathway remains poorly understood. Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins, ubiquitin-like modifiers that are required for the growth of autophagosomal membranes. In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes. Thus, Nix functions as an autophagy receptor, which mediates mitochondrial clearance after mitochondrial damage and during erythrocyte differentiation.
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              Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization.

              Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.
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                Author and article information

                Contributors
                i.ganley@dundee.ac.uk
                Journal
                FEBS J
                FEBS J
                10.1111/(ISSN)1742-4658
                FEBS
                The Febs Journal
                John Wiley and Sons Inc. (Hoboken )
                1742-464X
                1742-4658
                01 December 2017
                April 2018
                : 285
                : 7 ( doiID: 10.1111/febs.2018.285.issue-7 )
                : 1185-1202
                Affiliations
                [ 1 ] MRC Protein Phosphorylation and Ubiquitylation Unit School of Life Sciences University of Dundee UK
                Author notes
                [*] [* ] Correspondence

                I. G. Ganley, MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK

                Fax: +44 1382 223778

                Tel: +44 1382 388905

                E‐mail: i.ganley@ 123456dundee.ac.uk

                Article
                FEBS14336
                10.1111/febs.14336
                5947125
                29151277
                b0a1bcf2-087c-419b-89ce-7b2181470a16
                © 2017 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

                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
                : 14 August 2017
                : 09 October 2017
                : 14 November 2017
                Page count
                Figures: 3, Tables: 1, Pages: 18, Words: 11554
                Funding
                Funded by: Medical Research Council
                Award ID: MC_UU_12016/4
                Categories
                State‐of‐the‐Art Review
                State‐of‐the‐Art Review
                Custom metadata
                2.0
                febs14336
                April 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.8.2 mode:remove_FC converted:11.05.2018

                Molecular biology
                autophagy,development,disease,metabolism,mitochondria,mitophagy,mito‐qc,mouse models,nix,parkin
                Molecular biology
                autophagy, development, disease, metabolism, mitochondria, mitophagy, mito‐qc, mouse models, nix, parkin

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