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      The genetics and pathology of mitochondrial disease

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          Abstract

          Mitochondria are double‐membrane‐bound organelles that are present in all nucleated eukaryotic cells and are responsible for the production of cellular energy in the form of ATP. Mitochondrial function is under dual genetic control – the 16.6‐kb mitochondrial genome, with only 37 genes, and the nuclear genome, which encodes the remaining ∼1300 proteins of the mitoproteome. Mitochondrial dysfunction can arise because of defects in either mitochondrial DNA or nuclear mitochondrial genes, and can present in childhood or adulthood in association with vast clinical heterogeneity, with symptoms affecting a single organ or tissue, or multisystem involvement. There is no cure for mitochondrial disease for the vast majority of mitochondrial disease patients, and a genetic diagnosis is therefore crucial for genetic counselling and recurrence risk calculation, and can impact on the clinical management of affected patients. Next‐generation sequencing strategies are proving pivotal in the discovery of new disease genes and the diagnosis of clinically affected patients; mutations in >250 genes have now been shown to cause mitochondrial disease, and the biochemical, histochemical, immunocytochemical and neuropathological characterization of these patients has led to improved diagnostic testing strategies and novel diagnostic techniques. This review focuses on the current genetic landscape associated with mitochondrial disease, before focusing on advances in studying associated mitochondrial pathology in two, clinically relevant organs – skeletal muscle and brain. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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          Most cited references142

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          Crystal structure of the entire respiratory complex I

          Complex I is the first and largest enzyme of the respiratory chain, playing a central role in cellular energy production by coupling electron transfer between NADH and ubiquinone to proton translocation. It is implicated in many common human neurodegenerative diseases. Here we report the first crystal structure of the entire, intact complex I (from T. thermophilus) at 3.3 Å resolution. The structure of the 536 kDa complex comprises 16 different subunits with 64 transmembrane helices and 9 Fe-S clusters. The core fold of subunit Nqo8 (NuoH/ND1) is, unexpectedly, similar to a half-channel of the antiporter-like subunits. Small subunits nearby form a linked second half-channel, thus completing the fourth proton translocation pathway, in addition to the channels in three antiporter-like subunits. The quinone-binding site is unusually long, narrow and enclosed. The quinone headgroup binds at the deep end of this chamber, near cluster N2. Strikingly, the chamber is linked to the fourth channel by a “funnel” of charged residues. The link continues over the entire membrane domain as a remarkable flexible central axis of charged and polar residues. It likely plays a leading role in the propagation of conformational changes, aided by coupling elements. The structure suggests that a unique, out-of-the-membrane quinone reaction chamber allows the redox energy to drive concerted long-range conformational changes in the four antiporter-like domains, resulting in translocation of four protons per cycle.
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            Mitochondria and calcium: from cell signalling to cell death.

            M R Duchen (2000)
            While a pathway for Ca2+ accumulation into mitochondria has long been established, its functional significance is only now becoming clear in relation to cell physiology and pathophysiology. The observation that mitochondria take up Ca2+ during physiological Ca2+ signalling in a variety of cell types leads to four questions: (i) 'What is the impact of mitochondrial Ca2+ uptake on mitochondrial function?' (ii) 'What is the impact of mitochondrial Ca2+ uptake on Ca2+ signalling?' (iii) 'What are the consequences of impaired mitochondrial Ca2+ uptake for cell function?' and finally (iv) 'What are the consequences of pathological [Ca2+]c signalling for mitochondrial function?' These will be addressed in turn. Thus: (i) accumulation of Ca2+ into mitochondria regulates mitochondrial metabolism and causes a transient depolarisation of mitochondrial membrane potential. (ii) Mitochondria may act as a spatial Ca2+ buffer in many cells, regulating the local Ca2+ concentration in cellular microdomains. This process regulates processes dependent on local cytoplasmic Ca2+ concentration ([Ca2+]c), particularly the flux of Ca2+ through IP3-gated channels of the endoplasmic reticulum (ER) and the channels mediating capacitative Ca2+ influx through the plasma membrane. Consequently, mitochondrial Ca2+ uptake plays a substantial role in shaping [Ca2+]c signals in many cell types. (iii) Impaired mitochondrial Ca2+ uptake alters the spatiotemporal characteristics of cellular [Ca2+]c signalling and downregulates mitochondrial metabolism. (iv) Under pathological conditions of cellular [Ca2+]c overload, particularly in association with oxidative stress, mitochondrial Ca2+ uptake may trigger pathological states that lead to cell death. In the model of glutamate excitotoxicity, microdomains of [Ca2+]c are apparently central, as the pathway to cell death seems to require the local activation of neuronal nitric oxide synthase (nNOS), itself held by scaffolding proteins in close association with the NMDA receptor. Mitochondrial Ca2+ uptake in combination with NO production triggers the collapse of mitochondrial membrane potential, culminating in delayed cell death.
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              Mitochondrial complex I.

              Judy Hirst (2013)
              Complex I (NADH:ubiquinone oxidoreductase) is crucial for respiration in many aerobic organisms. In mitochondria, it oxidizes NADH from the tricarboxylic acid cycle and β-oxidation, reduces ubiquinone, and transports protons across the inner membrane, contributing to the proton-motive force. It is also a major contributor to cellular production of reactive oxygen species. The redox reaction of complex I is catalyzed in the hydrophilic domain; it comprises NADH oxidation by a flavin mononucleotide, intramolecular electron transfer along a chain of iron-sulfur clusters, and ubiquinone reduction. Redox-coupled proton translocation in the membrane domain requires long-range energy transfer through the protein complex, and the molecular mechanisms that couple the redox and proton-transfer half-reactions are currently unknown. This review evaluates extant data on the mechanisms of energy transduction and superoxide production by complex I, discusses contemporary mechanistic models, and explores how mechanistic studies may contribute to understanding the roles of complex I dysfunctions in human diseases.
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                Author and article information

                Contributors
                robert.taylor@ncl.ac.uk
                Journal
                J Pathol
                J. Pathol
                10.1002/(ISSN)1096-9896
                PATH
                The Journal of Pathology
                John Wiley & Sons, Ltd (Chichester, UK )
                0022-3417
                1096-9896
                02 November 2016
                January 2017
                : 241
                : 2 , The Genetics of Disease ( doiID: 10.1002/path.2017.241.issue-2 )
                : 236-250
                Affiliations
                [ 1 ] Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School Newcastle University Newcastle upon TyneUK
                Author notes
                [*] [* ]Correspondence to: R Taylor, Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. E‐mail: robert.taylor@ 123456ncl.ac.uk
                Article
                PATH4809
                10.1002/path.4809
                5215404
                27659608
                4f49f741-b01b-4430-9638-2351aa5c1f1f
                © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 31 August 2016
                : 15 September 2016
                : 16 September 2016
                Page count
                Figures: 6, Tables: 0, Pages: 15, Words: 8879
                Funding
                Funded by: Wellcome Trust Strategic Award
                Award ID: 096919/Z/11/Z
                Funded by: MRC Centre for Neuromuscular Diseases
                Award ID: G0601943
                Funded by: Newcastle University Centre for Ageing and Vitality
                Funded by: Biotechnology and Biological Sciences Research Council
                Funded by: Medical Research Council
                Award ID: G016354/1
                Funded by: Newcastle upon Tyne Hospitals NHS Foundation
                Funded by: MRC/ESPRC Newcastle Molecular Pathology Node
                Funded by: Lily Foundation
                Funded by: National Institute for Health Research (NIHR)
                Award ID: NIHR‐HCS‐D12‐03‐04
                Categories
                Invited Review
                Invited Reviews
                Custom metadata
                2.0
                path4809
                January 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.0 mode:remove_FC converted:05.01.2017

                Pathology
                mitochondria,mitochondrial disease,mtdna,respiratory chain deficiency,genetic diagnosis,muscle pathology,immunohistochemistry,neuropathology

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