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      DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass

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          Abstract

          Mitochondrial quality control is essential in highly structured cells such as neurons and muscles. In skeletal muscle the mitochondrial fission proteins are reduced in different physiopathological conditions including ageing sarcopenia, cancer cachexia and chemotherapy-induced muscle wasting. However, whether mitochondrial fission is essential for muscle homeostasis is still unclear. Here we show that muscle-specific loss of the pro-fission dynamin related protein (DRP) 1 induces muscle wasting and weakness. Constitutive Drp1 ablation in muscles reduces growth and causes animal death while inducible deletion results in atrophy and degeneration. Drp1 deficient mitochondria are morphologically bigger and functionally abnormal. The dysfunctional mitochondria signals to the nucleus to induce the ubiquitin-proteasome system and an Unfolded Protein Response while the change of mitochondrial volume results in an increase of mitochondrial Ca 2+ uptake and myofiber death. Our findings reveal that morphology of mitochondrial network is critical for several biological processes that control nuclear programs and Ca 2+ handling.

          Abstract

          Muscle loss is associated with altered expression of proteins involved in mitochondrial homeostasis, but whether this is causative remains unclear. Here, the authors show that genetic ablation of the pro-fission protein DRP1 leads to accumulation of abnormal mitochondria that induce muscle atrophy by altering Ca 2+ homeostasis and cellular stress responses.

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          Most cited references 45

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          Organelle isolation: functional mitochondria from mouse liver, muscle and cultured fibroblasts.

          Mitochondria participate in key metabolic reactions of the cell and regulate crucial signaling pathways including apoptosis. Although several approaches are available to study mitochondrial function in situ are available, investigating functional mitochondria that have been isolated from different tissues and from cultured cells offers still more unmatched advantages. This protocol illustrates a step-by-step procedure to obtain functional mitochondria with high yield from cells grown in culture, liver and muscle. The isolation procedures described here require 1-2 hours, depending on the source of the organelles. The polarographic analysis can be completed in 1 hour.
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            Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice.

            Mitochondrial morphology is dynamically controlled by a balance between fusion and fission. The physiological importance of mitochondrial fission in vertebrates is less clearly defined than that of mitochondrial fusion. Here we show that mice lacking the mitochondrial fission GTPase Drp1 have developmental abnormalities, particularly in the forebrain, and die after embryonic day 12.5. Neural cell-specific (NS) Drp1(-/-) mice die shortly after birth as a result of brain hypoplasia with apoptosis. Primary culture of NS-Drp1(-/-) mouse forebrain showed a decreased number of neurites and defective synapse formation, thought to be due to aggregated mitochondria that failed to distribute properly within the cell processes. These defects were reflected by abnormal forebrain development and highlight the importance of Drp1-dependent mitochondrial fission within highly polarized cells such as neurons. Moreover, Drp1(-/-) murine embryonic fibroblasts and embryonic stem cells revealed that Drp1 is required for a normal rate of cytochrome c release and caspase activation during apoptosis, although mitochondrial outer membrane permeabilization, as examined by the release of Smac/Diablo and Tim8a, may occur independently of Drp1 activity.
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              Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.

              Autophagy is crucial in the turnover of cell components, and clearance of damaged organelles by the autophagic-lysosomal pathway is essential for tissue homeostasis. Defects of this degradative system have a role in various diseases, but little is known about autophagy in muscular dystrophies. We have previously found that muscular dystrophies linked to collagen VI deficiency show dysfunctional mitochondria and spontaneous apoptosis, leading to myofiber degeneration. Here we demonstrate that this persistence of abnormal organelles and apoptosis are caused by defective autophagy. Skeletal muscles of collagen VI-knockout (Col6a1(-/-)) mice had impaired autophagic flux, which matched the lower induction of beclin-1 and BCL-2/adenovirus E1B-interacting protein-3 (Bnip3) and the lack of autophagosomes after starvation. Forced activation of autophagy by genetic, dietary and pharmacological approaches restored myofiber survival and ameliorated the dystrophic phenotype of Col6a1(-/-) mice. Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3. These findings indicate that defective activation of the autophagic machinery is pathogenic in some congenital muscular dystrophies.
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                Author and article information

                Contributors
                leonardo.salviati@unipd.it
                marco.sandri@unipd.it
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                12 June 2019
                12 June 2019
                2019
                : 10
                Affiliations
                [1 ]GRID grid.428736.c, Venetian Institute of Molecular Medicine, ; via Orus 2, 35129 Padova, Italy
                [2 ]ISNI 0000 0004 1757 3470, GRID grid.5608.b, Department of Biomedical Science, , University of Padova, ; via G. Colombo 3, 35100 Padova, Italy
                [3 ]ISNI 0000 0004 1757 3470, GRID grid.5608.b, Myology Center, , University of Padova, ; via G. Colombo 3, 35100 Padova, Italy
                [4 ]ISNI 0000 0004 1757 3470, GRID grid.5608.b, Department of Biology, , University of Padova, ; via U. Bassi 58B, 35121 Padova, Italy
                [5 ]ISNI 0000 0004 1757 3470, GRID grid.5608.b, Clinical Genetics Unit, Department of Woman and Child Health, , University of Padova, ; via Giustiniani 3, 35128 Padova, Italy
                [6 ]IRP Città della Speranza Corso Stati Uniti 4, 35127 Padova, Italy
                [7 ]ISNI 0000 0004 1757 3470, GRID grid.5608.b, Department of Medicine - DIMED, , University of Padova, ; 35128 Padova, Italy
                [8 ]ISNI 0000 0001 2181 4941, GRID grid.412451.7, Center for Research on Ageing and Translational Medicine (CeSI-MeT)), , via Luigi Polacchi, University G. d’ Annunzio, ; 66100 Chieti, Italy
                [9 ]Institute for Kinesiology Research, Science and Research Center of Koper, Koper, Slovenia
                [10 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Department of Medicine, , McGill University, ; Montreal, Canada
                Article
                10226
                10.1038/s41467-019-10226-9
                6561930
                31189900
                © The Author(s) 2019

                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/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100010663, EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council);
                Award ID: 282310
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100010665, EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Skłodowska-Curie Actions (H2020 Excellent Science - Marie Skłodowska-Curie Actions);
                Award ID: 645648
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004923, AFM-Téléthon (French Muscular Dystrophy Association);
                Award ID: 19524
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001674, Fondation Leducq;
                Funded by: FundRef https://doi.org/10.13039/100007479, Fondazione Cassa di Risparmio di Padova e Rovigo (Foundation Cariparo);
                Funded by: FundRef https://doi.org/10.13039/501100002426, Fondazione Telethon (Telethon Foundation);
                Award ID: GGP13213
                Award ID: GGP14187c
                Award Recipient :
                Categories
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                © The Author(s) 2019

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                mitophagy, energy metabolism, skeletal muscle

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