Lateral pH gradient between OXPHOS complex IV and F0F1 ATP-synthase in folded mitochondrial membranes

Rieger, Bettina; Junge, Wolfgang; Busch, Karin B.

doi:10.1038/ncomms4103

Cited by 128 publications

(91 citation statements)

References 34 publications

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“…7 Cristae architecture may be important for producing an optimal distance between residing electron transporting chain complexes, specifically between complex III/IV supercomplexes, localized at lamellar regions, and ATP synthase oligomers localized to the curved edges. [14][15][16][17] This is the first description of a defect in a MICOS subunit in human. As predicted from previously reported yeast observations our analysis shows that the MICOS assembly plays an essential role in mitochondrial respiratory chain function.…”

Section: Discussionmentioning

confidence: 86%

Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit

et al. 2016

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The mitochondrial inner membrane possesses distinct subdomains including cristae, which are lamellar structures invaginated into the mitochondrial matrix and contain the respiratory complexes. Generation of inner membrane domains requires the complex interplay between the respiratory complexes, mitochondrial lipids and the recently identified mitochondrial contact site and cristae organizing system (MICOS) complex. Proper organization of the mitochondrial inner membrane has recently been shown to be important for respiratory function in yeast. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with a neurodegenerative disorder accompanied by hyperlactatemia, 3-methylglutaconic aciduria, disturbed hepatocellular function with abnormal cristae morphology in liver and cerebellar and vermis atrophy, which suggest mitochondrial dysfunction. Using homozygosity mapping and exome sequencing the patients were found to be homozygous for the p.(Gly15Glufs*75) variant in the QIL1/MIC13 (C19orf70) gene. QIL1/MIC13 is a constituent of MICOS, a six subunit complex that helps to form and/or stabilize cristae junctions and determine the placement, distribution and number of cristae within mitochondria. In patient fibroblasts both MICOS subunits QIL1/MIC13 and MIC10 were absent whereas MIC60 was present in a comparable abundance to that of the control. We conclude that QIL1/MIC13 deficiency in human, is associated with disassembly of the MICOS complex, with the associated aberration of cristae morphology and mitochondrial respiratory dysfunction. 3-Methylglutaconic aciduria is associated with variants in genes encoding mitochondrial inner membrane organizing determinants, including TAZ, DNAJC19, SERAC1 and QIL1/MIC13.

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Section: Discussionmentioning

confidence: 86%

Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit

et al. 2016

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“…It suggests that proton uptake (or release) transpires at the membrane surface (31) and does not occur from the bulk of the mitochondrial matrix or the bulk of the intermembrane space. As a result of both the membrane proteins' activity and proton surface to bulk release, the local surface proton concentration varies along the membrane (32,33). It implies that proteins colocalized with the proton pumps on the CM (e.g., ATP synthase) (34,35) will experience the highest pmf, whereas the pmf is much lower for proteins localized at the IBM (e.g., UCP4).…”

Section: Resultsmentioning

confidence: 99%

Superresolution microscopy reveals spatial separation of UCP4 and F ₀ F ₁ -ATP synthase in neuronal mitochondria

Klotzsch

Smorodchenko²,

Löfler

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Because different proteins compete for the proton gradient across the inner mitochondrial membrane, an efficient mechanism is required for allocation of associated chemical potential to the distinct demands, such as ATP production, thermogenesis, regulation of reactive oxygen species (ROS), etc. Here, we used the superresolution technique dSTORM (direct stochastic optical reconstruction microscopy) to visualize several mitochondrial proteins in primary mouse neurons and test the hypothesis that uncoupling protein 4 (UCP4) and F 0 F 1 -ATP synthase are spatially separated to eliminate competition for the proton motive force. We found that UCP4, F 0 F 1 -ATP synthase, and the mitochondrial marker voltage-dependent anion channel (VDAC) have various expression levels in different mitochondria, supporting the hypothesis of mitochondrial heterogeneity. Our experimental results further revealed that UCP4 is preferentially localized in close vicinity to VDAC, presumably at the inner boundary membrane, whereas F 0 F 1 -ATP synthase is more centrally located at the cristae membrane. The data suggest that UCP4 cannot compete for protons because of its spatial separation from both the proton pumps and the ATP synthase. Thus, mitochondrial morphology precludes UCP4 from acting as an uncoupler of oxidative phosphorylation but is consistent with the view that UCP4 may dissipate the excessive proton gradient, which is usually associated with ROS production. mitochondrial membrane proteins | proton diffusion | direct stochastic optical reconstruction microscopy | uncoupling | reactive oxygen species M itochondria are involved in a wide range of cell functions, including fatty acid oxidation, calcium homeostasis, apoptosis, reactive oxygen species (ROS) signaling, and above all, production of ATP (1, 2). In neurons, these organelles are transported along neuronal processes to provide energy for areas of high energy demand, such as synapses (3). To support their functions, mitochondria exhibit a complex morphology consisting of separate and functionally distinct outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM). The latter is structurally organized into two domains: an inner boundary membrane (IBM) and a cristae membrane (CM) (4). The current hypotheses imply that the morphology/topology of the IMM is tightly related to biochemical function, the energy state, and the pathophysiological state of mitochondria (5). Whereas the OMM contains porins [e.g., voltage-dependent anion channel (VDAC)], which mediate its permeability to molecules up to 10 kDa, the IMM topology is highly complex. It is comprised of different transport proteins, the ATP synthase (complex V), and complexes I, III, and IV of the electron transport chain, which are responsible for generating the proton motive force (pmf); pmf represents the driving force for not only ATP synthesis, but also other protein-mediated transport activities (for example, phosphate, pyruvate, and glutamate transport). Uncoupling protein 1 (UCP1; thermogenin), a memb...

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“…However, in a more recent study that describes the in situ separation of respiratory chain complexes and ATP synthase dimers, it was suggested that protons travel from source to sink along a pH gradient (19). Using ratiometric GFP constructs, it was shown that in actively respiring mitochondria of HeLa cells, the pH on the luminal side of the cytochrome c oxidase (a proton source that pumps protons into the cristae space) is 0.3 units lower than at the ATP synthase dimer (the proton sink) (38). In P. tetraurelia, the formation of helical arrays of ATP synthase dimers would also separate proton sources and sinks and hence result in the formation of a local pH gradient, as reported for HeLa cells.…”

Section: Discussionmentioning

confidence: 99%

Helical arrays of U-shaped ATP synthase dimers form tubular cristae in ciliate mitochondria

Muhleip

Joos

Wigge

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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F 1 F o -ATP synthases are universal energy-converting membrane protein complexes that synthesize ATP from ADP and inorganic phosphate. In mitochondria of yeast and mammals, the ATP synthase forms V-shaped dimers, which assemble into rows along the highly curved ridges of lamellar cristae. Using electron cryotomography and subtomogram averaging, we have determined the in situ structure and organization of the mitochondrial ATP synthase dimer of the ciliate Paramecium tetraurelia. The ATP synthase forms U-shaped dimers with parallel monomers. Each complex has a prominent intracrista domain, which links the c-ring of one monomer to the peripheral stalk of the other. Close interaction of intracrista domains in adjacent dimers results in the formation of helical ATP synthase dimer arrays, which differ from the loose dimer rows in all other organisms observed so far. The parameters of the helical arrays match those of the cristae tubes, suggesting the unique features of the P. tetraurelia ATP synthase are directly responsible for generating the helical tubular cristae. We conclude that despite major structural differences between ATP synthase dimers of ciliates and other eukaryotes, the formation of ATP synthase dimer rows is a universal feature of mitochondria and a fundamental determinant of cristae morphology.cryoelectron microscopy | subtomogram averaging | Paramecium | macromolecular organization | serial block face imaging F 1 F o -ATP synthases are ubiquitous, highly conserved energyconverting membrane protein complexes. ATP synthases produce ATP from ADP and inorganic phosphate (P i ) by rotary catalysis (1, 2) using the energy stored in a transmembrane electrochemical gradient. The ∼600-kDa monomer of the mitochondrial ATP synthase is composed of a soluble F 1 subcomplex and a membranebound F o subcomplex (3). The main components of the F 1 subcomplex are the (αβ) 3 hexamer and the central stalk (4). The F o subcomplex includes a rotor ring of 8-15 hydrophobic c subunits (5), the peripheral stalk, and several small hydrophobic stator subunits. Protons flowing through the membrane part of the F o subcomplex drive the rotation of the c-ring (6-9). The central stalk transmits the torque generated by c-ring rotation to the catalytic head of the F 1 subcomplex, where it induces conformational changes of the α and β subunits that result in phosphate bond formation and the generation of ATP. The catalytic (αβ) 3 hexamer is held stationary relative to the membrane region by the peripheral stalk (10, 11). Several high-resolution structures of the F 1 /rotor ring complexes have been solved by X-ray crystallography (12-16), and the structure of the complete assembly has been determined by cryoelectron microscopy (cryo-EM) (10,(17)(18)(19)(20).In mitochondria, the ATP synthase forms dimers in the inner membrane. In fungi, plants, and metazoans, the dimers are V-shaped and associate into rows along the highly curved ridges of lamellar cristae (19)(20)(21)(22). F o subcomplexes of the two monomers in the dimer interact in...

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Lateral pH gradient between OXPHOS complex IV and F0F1 ATP-synthase in folded mitochondrial membranes

Cited by 128 publications

References 34 publications

Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit

Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit

Superresolution microscopy reveals spatial separation of UCP4 and F ₀ F ₁ -ATP synthase in neuronal mitochondria

Helical arrays of U-shaped ATP synthase dimers form tubular cristae in ciliate mitochondria

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Lateral pH gradient between OXPHOS complex IV and F0F1 ATP-synthase in folded mitochondrial membranes

Cited by 128 publications

References 34 publications

Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit

Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit

Superresolution microscopy reveals spatial separation of UCP4 and F 0 F 1 -ATP synthase in neuronal mitochondria

Helical arrays of U-shaped ATP synthase dimers form tubular cristae in ciliate mitochondria

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Superresolution microscopy reveals spatial separation of UCP4 and F ₀ F ₁ -ATP synthase in neuronal mitochondria