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      Mitochondrial Cristae Shape Determines Respiratory Chain Supercomplexes Assembly and Respiratory Efficiency

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          Summary

          Respiratory chain complexes assemble into functional quaternary structures called supercomplexes (RCS) within the folds of the inner mitochondrial membrane, or cristae. Here, we investigate the relationship between respiratory function and mitochondrial ultrastructure and provide evidence that cristae shape determines the assembly and stability of RCS and hence mitochondrial respiratory efficiency. Genetic and apoptotic manipulations of cristae structure affect assembly and activity of RCS in vitro and in vivo, independently of changes to mitochondrial protein synthesis or apoptotic outer mitochondrial membrane permeabilization. We demonstrate that, accordingly, the efficiency of mitochondria-dependent cell growth depends on cristae shape. Thus, RCS assembly emerges as a link between membrane morphology and function.

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          Highlights

          • Dissociation of cristae remodeling from OMM permeabilization

          • Cristae shape determines assembly of respiratory chain supercomplexes

          • Efficiency of mitochondrial respiration and cellular growth depends on cristae shape

          Abstract

          The ability to perturb cristae shape without affecting other key aspects of mitochondrial physiology reveals that membrane shape influences supercomplex assembly and stability to regulate mitochondrial respiration and cellular respiratory growth. Quaternary structures such as supercomplexes therefore emerge as a link between membrane morphology and function.

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          Most cited references30

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          Cell death: critical control points.

          Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics.
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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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              Supercomplex assembly determines electron flux in the mitochondrial electron transport chain.

              The textbook description of mitochondrial respiratory complexes (RCs) views them as free-moving entities linked by the mobile carriers coenzyme Q (CoQ) and cytochrome c (cyt c). This model (known as the fluid model) is challenged by the proposal that all RCs except complex II can associate in supercomplexes (SCs). The proposed SCs are the respirasome (complexes I, III, and IV), complexes I and III, and complexes III and IV. The role of SCs is unclear, and their existence is debated. By genetic modulation of interactions between complexes I and III and III and IV, we show that these associations define dedicated CoQ and cyt c pools and that SC assembly is dynamic and organizes electron flux to optimize the use of available substrates.
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                Author and article information

                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                26 September 2013
                26 September 2013
                : 155
                : 1
                : 160-171
                Affiliations
                [1 ]Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy
                [2 ]Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy
                [3 ]IRCCS Fondazione Santa Lucia, Via Ardeatina 306, 00143 Rome, Italy
                [4 ]Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy
                [5 ]Centro Nacional de Investigaciònes Cardiovasculares Carlos III, Melchor Fernàndez Almagro 3, 28029 Madrid, Spain
                [6 ]Departamento de Bioquìmica y Biologia Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Pedro Cerbuna 12, 50009 Zaragoza, Spain
                Author notes
                []Corresponding author jaenriquez@ 123456cnic.es
                [∗∗ ]Corresponding author luca.scorrano@ 123456unipd.it
                Article
                S0092-8674(13)01026-X
                10.1016/j.cell.2013.08.032
                3790458
                24055366
                179f2d51-4c52-446d-80c6-ea321ca52c16
                © 2013 The Authors

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 28 December 2012
                : 25 July 2013
                : 19 August 2013
                Categories
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                Cell biology
                Cell biology

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