Mitochondrial Disease

2021 ◽  
pp. 1126-1133
Author(s):  
Radhika Dhamija ◽  
Erin Conboy ◽  
Ralitza H. Gavrilova
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Membrane ◽  
Protein Complexes ◽  
Mitochondrial Diseases ◽  
Mendelian Inheritance ◽  
Inner Mitochondrial Membrane ◽  
Oxidative Phosphorylation System ◽  
Transport Chain ◽  
Membrane Bound ◽  
Multimeric Protein

Primary mitochondrial diseases are a heterogeneous group of disorders that result from defects of the oxidative phosphorylation system of the mitochondria. Often underrecognized, mitochondrial diseases are uncommon (estimated incidence, 1 in 10,000 live births). Mitochondria are double-membrane–bound cytoplasmic organelles whose primary function is to provide energy (ie, adenosine triphosphate [ATP]) from the breakdown of carbohydrates, protein, and lipids by means of the electron transport chain and the oxidative phosphorylation system. The respiratory chain of mitochondria, located in the inner mitochondrial membrane, consists of 5 multimeric protein complexes (complexes I-IV and ATP synthase [complex V]). The structural proteins of these complexes are encoded by both mitochondrial and nuclear genes. Therefore, primary mitochondrial disorders can follow a maternal or mendelian inheritance pattern.

scholarly journals DRP1 regulates endoplasmic reticulum sheets to control mitochondrial DNA replication and segregation

2021 ◽  
Author(s):  
Hema Saranya Ilamathi ◽  
Sara Benhammouda ◽  
Justine Desrochers-Goyette ◽  
Matthew A Lines ◽  
Marc Germain
Keyword(s):  
Endoplasmic Reticulum ◽  
Mitochondrial Dna ◽  
Protein Complexes ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Diseases ◽  
Contact Sites ◽  
Transport Chain ◽  
Essential Components ◽  
Mtdna Replication

Mitochondria are multi-faceted organelles crucial for cellular homeostasis that contain their own genome. Mitochondrial DNA (mtDNA) codes for several essential components of the electron transport chain, and mtDNA maintenance defects lead to mitochondrial diseases. mtDNA replication occurs at endoplasmic reticulum (ER)-mitochondria contact sites and is regulated by mitochondrial dynamics. Specifically, mitochondrial fusion is essential for mtDNA maintenance. In contrast, while loss of mitochondrial fission causes the aggregation of nucleoids (mtDNA-protein complexes), its role in nucleoid distribution remains unclear. Here, we show that the mitochondrial fission protein DRP1 regulates nucleoid segregation by altering ER sheets, the ER structure associated with protein synthesis. Specifically, DRP1 loss or mutation leads to altered ER sheets that physically interact with mitobulbs, mitochondrial structures containing aggregated nucleoids. Importantly, nucleoid distribution and mtDNA replication were rescued by expressing the ER sheet protein CLIMP63. Thus, our work identifies a novel mechanism by which DRP1 regulates mtDNA replication and distribution.

scholarly journals Stress signalling dynamics of the mitochondrial electron transport chain and oxidative phosphorylation system in higher plants

2019 ◽  
Vol 125 (5) ◽  
pp. 721-736 ◽  
Author(s):  
Corentin Dourmap ◽  
Solène Roque ◽  
Amélie Morin ◽  
Damien Caubrière ◽  
Margaux Kerdiles ◽  
...  
Keyword(s):  
Climate Change ◽  
Electron Transport ◽  
Oxidative Phosphorylation ◽  
Electron Transport Chain ◽  
Plant Mitochondria ◽  
Mitochondrial Electron Transport Chain ◽  
Oxidative Phosphorylation System ◽  
Transport Chain ◽  
Wide Range ◽  
Stress Signalling

Abstract Background Mitochondria play a diversity of physiological and metabolic roles under conditions of abiotic or biotic stress. They may be directly subjected to physico-chemical constraints, and they are also involved in integrative responses to environmental stresses through their central position in cell nutrition, respiration, energy balance and biosyntheses. In plant cells, mitochondria present various biochemical peculiarities, such as cyanide-insensitive alternative respiration, and, besides integration with ubiquitous eukaryotic compartments, their functioning must be coupled with plastid functioning. Moreover, given the sessile lifestyle of plants, their relative lack of protective barriers and present threats of climate change, the plant cell is an attractive model to understand the mechanisms of stress/organelle/cell integration in the context of environmental stress responses. Scope The involvement of mitochondria in this integration entails a complex network of signalling, which has not been fully elucidated, because of the great diversity of mitochondrial constituents (metabolites, reactive molecular species and structural and regulatory biomolecules) that are linked to stress signalling pathways. The present review analyses the complexity of stress signalling connexions that are related to the mitochondrial electron transport chain and oxidative phosphorylation system, and how they can be involved in stress perception and transduction, signal amplification or cell stress response modulation. Conclusions Plant mitochondria are endowed with a diversity of multi-directional hubs of stress signalling that lead to regulatory loops and regulatory rheostats, whose functioning can amplify and diversify some signals or, conversely, dampen and reduce other signals. Involvement in a wide range of abiotic and biotic responses also implies that mitochondrial stress signalling could result in synergistic or conflicting outcomes during acclimation to multiple and complex stresses, such as those arising from climate change.

scholarly journals Molecular mechanism of mitochondrial phosphatidate transfer by Ups1

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Jiuwei Lu ◽  
Chun Chan ◽  
Leiye Yu ◽  
Jun Fan ◽  
Fei Sun ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Mitochondrial Membrane ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Membranes ◽  
Inner Mitochondrial Membrane ◽  
Membrane Interaction ◽  
Detailed Mechanism ◽  
Physiological Regulator ◽  
Membrane Bound ◽  
Dynamics Simulations

AbstractCardiolipin, an essential mitochondrial physiological regulator, is synthesized from phosphatidic acid (PA) in the inner mitochondrial membrane (IMM). PA is synthesized in the endoplasmic reticulum and transferred to the IMM via the outer mitochondrial membrane (OMM) under mediation by the Ups1/Mdm35 protein family. Despite the availability of numerous crystal structures, the detailed mechanism underlying PA transfer between mitochondrial membranes remains unclear. Here, a model of Ups1/Mdm35-membrane interaction is established using combined crystallographic data, all-atom molecular dynamics simulations, extensive structural comparisons, and biophysical assays. The α2-loop, L2-loop, and α3 helix of Ups1 mediate membrane interactions. Moreover, non-complexed Ups1 on membranes is found to be a key transition state for PA transfer. The membrane-bound non-complexed Ups1/ membrane-bound Ups1 ratio, which can be regulated by environmental pH, is inversely correlated with the PA transfer activity of Ups1/Mdm35. These results demonstrate a new model of the fine conformational changes of Ups1/Mdm35 during PA transfer.

Two Forms of a Mitochondrial Endonuclease in Neurospora crassa

1975 ◽  
Vol 53 (7) ◽  
pp. 823-825 ◽  
Author(s):  
Charles E. Martin ◽  
Robert P. Wagner
Keyword(s):  
Molecular Weight ◽  
Neurospora Crassa ◽  
Mitochondrial Membrane ◽  
Nuclease Activity ◽  
Inner Mitochondrial Membrane ◽  
Detergent Treatment ◽  
Approximate Molecular Weight ◽  
Membrane Bound

Mitochondrial nuclease activity in Neurospora crassa occurs in membrane-bound and soluble forms in approximately equal proportions. These activities apparently are due to the same enzyme, which has an approximate molecular weight of 120 000. A portion of the insoluble enzyme appears to be associated with the inner mitochondrial membrane and is resistant to solubilization by detergent treatment as well as by physical disruption methods.

scholarly journals The maturation of the inner membrane of foetal rat liver mitochondria. An example of a positive-feedback mechanism

1975 ◽  
Vol 150 (3) ◽  
pp. 477-488 ◽  
Author(s):  
J K Pollak
Keyword(s):  
Oxidative Phosphorylation ◽  
Rat Liver ◽  
Mitochondrial Membrane ◽  
Respiratory Control ◽  
Liver Mitochondria ◽  
Neonatal Rat ◽  
Rat Liver Mitochondria ◽  
Inner Mitochondrial Membrane ◽  
Mature Adult ◽  
Foetal Rat

A new method was devised for the isolation of foetal and neonatal rat lvier mitochondria, giving higher yields than conventional methods. 2. During development from the perinatal period to the mature adult, the ratio of cytochrome oxidase/succinate-cytochrome c reductase changes. 3. The inner mitochondrial membrane of foetal liver mitochondria possesses virtually no osmotic activity; the permeability to sucrose decreases with increasing developmental age. 4. Foetal rat liver mitochondria possess only marginal respiratory control and do not maintain Ca2+-induced respiration; they also swell in respiratory-control medium in the absence of substrate. ATP enhances respiratory control and prevents swelling, adenylyl imidodiphosphate, ATP+atractyloside enhance the R.C.I. (respiratory control index), Ca2+-induced respiratory control and prevent swelling, whereas GTP and low concentrations of ADP have none of these actions. It is concluded that the effect of ATP depends on steric interaction with the inner mitochondrial membrane. 5. When 1-day pre-partum foetuses are obtained by Caesarean section and maintained in a Humidicrib for 90 min, mitochondrial maturation is ‘triggered’, so that their R.C.I. is enhanced and no ATP is required to support Ca2+-dependent respiratory control or to inhibit mitochondrial swelling. 6. It is concluded that foetal rat liver mitochondria in utero do not respire, although they are capable of oxidative phosphorylation in spite of their low R.C.I. The different environmental conditions which the neonatal rat encounters ex utero enable the hepatic mitochondria to produce ATP, which interacts with the inner mitochondrial membrane to enhance oxidative phosphorylation by an autocatalytic mechanism.

scholarly journals A dual function of TMEM70 in OXPHOS: assembly of complexes I and V

2019 ◽  
Author(s):  
Laura Sánchez-Caballero ◽  
Dei M. Elurbe ◽  
Fabian Baertling ◽  
Sergio Guerrero-Castillo ◽  
Mariel van den Brand ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Congenital Defects ◽  
Dual Function ◽  
Inner Mitochondrial Membrane ◽  
Independent Evidence ◽  
Membrane Recruitment ◽  
Oxphos System ◽  
Membrane Bound ◽  
Assembly Intermediate ◽  
The Stability

AbstractProtein complexes from the oxidative phosphorylation (OXPHOS) system are assembled with the help of proteins called assembly factors. We here delineate the function of the inner mitochondrial membrane protein TMEM70, in which mutations have been linked to OXPHOS deficiencies, using a combination of BioID, complexome profiling and coevolution analyses. TMEM70 interacts with complex I and V and for both complexes the loss of TMEM70 results in the accumulation of an assembly intermediate followed by a reduction of the next assembly intermediate in the pathway. This indicates that TMEM70 has a role in the stability of membrane-bound subassemblies or in the membrane recruitment of subunits into the forming complex. Independent evidence for a role of TMEM70 in OXPHOS assembly comes from evolutionary analyses. The TMEM70/TMEM186/TMEM223 protein family, of which we show that TMEM186 and TMEM223 are mitochondrial in human as well, only occurs in species with OXPHOS complexes. Our results validate the use of combining complexomics with BioID and evolutionary analyses in elucidating congenital defects in protein complex assembly.

scholarly journals Membrane-tethering of cytochrome c accelerates regulated cell death in yeast

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Alexandra Toth ◽  
Andreas Aufschnaiter ◽  
Olga Fedotovskaya ◽  
Hannah Dawitz ◽  
Pia Ädelroth ◽  
...  
Keyword(s):  
Cell Death ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Membrane ◽  
Mitochondrial Respiratory Chain ◽  
Intermembrane Space ◽  
Inner Mitochondrial Membrane ◽  
Fitness Advantage ◽  
Regulated Cell Death ◽  
Membrane Tethering ◽  
Membrane Anchoring

Abstract Intrinsic apoptosis as a modality of regulated cell death is intimately linked to permeabilization of the outer mitochondrial membrane and subsequent release of the protein cytochrome c into the cytosol, where it can participate in caspase activation via apoptosome formation. Interestingly, cytochrome c release is an ancient feature of regulated cell death even in unicellular eukaryotes that do not contain an apoptosome. Therefore, it was speculated that cytochrome c release might have an additional, more fundamental role for cell death signalling, because its absence from mitochondria disrupts oxidative phosphorylation. Here, we permanently anchored cytochrome c with a transmembrane segment to the inner mitochondrial membrane of the yeast Saccharomyces cerevisiae, thereby inhibiting its release from mitochondria during regulated cell death. This cytochrome c retains respiratory growth and correct assembly of mitochondrial respiratory chain supercomplexes. However, membrane anchoring leads to a sensitisation to acetic acid-induced cell death and increased oxidative stress, a compensatory elevation of cellular oxygen-consumption in aged cells and a decreased chronological lifespan. We therefore conclude that loss of cytochrome c from mitochondria during regulated cell death and the subsequent disruption of oxidative phosphorylation is not required for efficient execution of cell death in yeast, and that mobility of cytochrome c within the mitochondrial intermembrane space confers a fitness advantage that overcomes a potential role in regulated cell death signalling in the absence of an apoptosome.

Mitochondrial ion circuits

2010 ◽  
Vol 47 ◽  
pp. 25-35 ◽  
Author(s):  
David G. Nicholls
Keyword(s):  
Electron Transport Chain ◽  
Mitochondrial Membrane ◽  
Primary Energy ◽  
Proton Leak ◽  
Primary Proton ◽  
Inner Mitochondrial Membrane ◽  
Intact Cells ◽  
Transport Chain ◽  
Proton Current ◽  
Circuit Techniques

Proton circuits across the inner mitochondrial membrane link the primary energy generators, namely the complexes of the electron transport chain, to multiple energy utilizing processes, including the ATP synthase, inherent proton leak pathways, metabolite transport and linked circuits of sodium and calcium. These mitochondrial circuits can be monitored in both isolated preparations and intact cells and, for the primary proton circuit techniques, exist to follow both the proton current and proton electrochemical potential components of the circuit in parallel experiments, providing a quantitative means of assessing mitochondrial function and, equally importantly, dysfunction.

scholarly journals Stepwise Assembly of Dimeric F1Fo-ATP Synthase in Mitochondria Involves the Small Fo-Subunits k and i

2010 ◽  
Vol 21 (9) ◽  
pp. 1494-1504 ◽  
Author(s):  
Karina Wagner ◽  
Inge Perschil ◽  
Christiane D. Fichter ◽  
Martin van der Laan
Keyword(s):  
Oxidative Phosphorylation ◽  
Atp Synthase ◽  
Mitochondrial Membrane ◽  
Intermediate Form ◽  
Membrane Domains ◽  
Inner Mitochondrial Membrane ◽  
F1fo Atp Synthase ◽  
Key Enzyme ◽  
Stepwise Assembly ◽  
Oligomeric Forms

F1Fo-ATP synthase is a key enzyme of oxidative phosphorylation that is localized in the inner membrane of mitochondria. It uses the energy stored in the proton gradient across the inner mitochondrial membrane to catalyze the synthesis of ATP from ADP and phosphate. Dimeric and higher oligomeric forms of ATP synthase have been observed in mitochondria from various organisms. Oligomerization of ATP synthase is critical for the morphology of the inner mitochondrial membrane because it supports the generation of tubular cristae membrane domains. Association of individual F1Fo-ATP synthase complexes is mediated by the membrane-embedded Fo-part. Several subunits were mapped to monomer-monomer-interfaces of yeast ATP synthase complexes, but only Su e (Atp21) and Su g (Atp20) have so far been identified as crucial for the formation of stable dimers. We show that two other small Fo-components, Su k (Atp19) and Su i (Atp18) are involved in the stepwise assembly of F1Fo-ATP synthase dimers and oligomers. We have identified an intermediate form of the ATP synthase dimer, which accumulates in the absence of Su i. Moreover, our data indicate that Su i facilitates the incorporation of newly synthesized subunits into ATP synthase complexes.

Role of cryo-ET in membrane bioenergetics research

2013 ◽  
Vol 41 (5) ◽  
pp. 1227-1234 ◽  
Author(s):  
Karen M. Davies ◽  
Bertram Daum
Keyword(s):  
Spatial Organization ◽  
Electron Tomography ◽  
Protein Complexes ◽  
Mitochondrial Diseases ◽  
Atp Synthesis ◽  
Cellular Level ◽  
Molecular Organization ◽  
Cellular Context ◽  
Membrane Bound ◽  
The Individual

To truly understand bioenergetic processes such as ATP synthesis, membrane-bound substrate transport or flagellar rotation, systems need to be analysed in a cellular context. Cryo-ET (cryo-electron tomography) is an essential part of this process, as it is currently the only technique which can directly determine the spatial organization of proteins at the level of both the cell and the individual protein complexes. The need to assess bioenergetic processes at a cellular level is becoming more and more apparent with the increasing interest in mitochondrial diseases. In recent years, cryo-ET has contributed significantly to our understanding of the molecular organization of mitochondria and chloroplasts. The present mini-review first describes the technique of cryo-ET and then discusses its role in membrane bioenergetics specifically in chloroplasts and mitochondrial research.

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