Frankfurt Institute for Molecular Life science

Frankfurt am Main, Germany

Frankfurt Institute for Molecular Life science

Frankfurt am Main, Germany
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Davies K.M.,Max Planck Institute of Biophysics | Strauss M.,Max Planck Institute of Biophysics | Daum B.,Max Planck Institute of Biophysics | Kief J.H.,Goethe University Frankfurt | And 5 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2011

We used electron cryotomography to study the molecular arrangement of large respiratory chain complexes in mitochondria from bovine heart, potato, and three types of fungi. Long rows of ATP synthase dimers were observed in intact mitochondria and cristae membrane fragments of all species that were examined. The dimer rows were found exclusively on tightly curved cristae edges. The distance between dimers along the rows varied, but within the dimer the distance between F 1 heads was constant. The angle between monomers in the dimer was 70° or above. Complex I appeared as L-shaped densities in tomograms of reconstituted proteoliposomes. Similar densities were observed in flat membrane regions of mitochondrial membranes from all species except Saccharomyces cerevisiae and identified as complex I by quantumdot labeling. The arrangement of respiratory chain proton pumps on flat cristae membranes and ATP synthase dimer rows along cristae edges was conserved in all species investigated. We propose that the supramolecular organization of respiratory chain complexes as proton sources and ATP synthase rows as proton sinks in the mitochondrial cristae ensures optimal conditions for efficient ATP synthesis.

Scheffer M.P.,European Molecular Biology Laboratory | Scheffer M.P.,Frankfurt Institute for Molecular Life science | Eltsov M.,European Molecular Biology Laboratory | Bednar J.,Joseph Fourier University | And 3 more authors.
Journal of Structural Biology | Year: 2012

In this study, electron tomograms of plunge-frozen isolated chromatin in both open and compacted form were recorded. We have resolved individual nucleosomes in these tomograms in order to provide a 3D view of the arrangement of nucleosomes within chromatin fibers at different compaction states. With an optimized template matching procedure we obtained accurate positions and orientations of nucleosomes in open chromatin in " low-salt" conditions (5mM NaCl). The mean value of the planar angle between three consecutive nucleosomes is 70°, and the mean center-to-center distance between consecutive nucleosomes is 22.3nm. Since the template matching approach was not effective in crowded conditions, for nucleosome detection in compact fibers (40mM NaCl and 1mM MgCl 2) we developed the nucleosome detection procedure based on the watershed algorithm, followed by sub-tomogram alignment, averaging, and classification by Principal Components Analysis. We find that in compact chromatin the nucleosomes are arranged with a predominant face-to-face stacking organization, which has not been previously shown for native isolated chromatin. Although the path of the DNA cannot be directly seen in compact conditions, it is evident that the nucleosomes stack with their dyad axis aligned in forming a " double track" conformation which is a consequence of DNA joining adjacent nucleosome stacks. Our data suggests that nucleosome stacking is an important mechanism for generating chromatin compaction in vivo. © 2011 Elsevier Inc..

Botelho S.C.,University of Stockholm | Osterberg M.,University of Stockholm | Reichert A.S.,Goethe University Frankfurt | Reichert A.S.,Frankfurt Institute for Molecular Life science | And 6 more authors.
EMBO Journal | Year: 2011

While overall hydrophobicity is generally recognized as the main characteristic of transmembrane (TM) β ±-helices, the only membrane system for which there are detailed quantitative data on how different amino acids contribute to the overall efficiency of membrane insertion is the endoplasmic reticulum (ER) of eukaryotic cells. Here, we provide comparable data for TIM23-mediated membrane protein insertion into the inner mitochondrial membrane of yeast cells. We find that hydrophobicity and the location of polar and aromatic residues are strong determinants of membrane insertion. These results parallel what has been found previously for the ER. However, we see striking differences between the effects elicited by charged residues flanking the TM segments when comparing the mitochondrial inner membrane and the ER, pointing to an unanticipated difference between the two insertion systems. © 2011 European Molecular Biology Organization | All Rights Reserved.

Leuner K.,Goethe University Frankfurt | Schutt T.,Goethe University Frankfurt | Kurz C.,Goethe University Frankfurt | Eckert S.H.,Goethe University Frankfurt | And 18 more authors.
Antioxidants and Redox Signaling | Year: 2012

Aims: Intracellular amyloid beta (Aβ) oligomers and extracellular Aβ plaques are key players in the progression of sporadic Alzheimer's disease (AD). Still, the molecular signals triggering Aβ production are largely unclear. We asked whether mitochondrion-derived reactive oxygen species (ROS) are sufficient to increase Aβ generation and thereby initiate a vicious cycle further impairing mitochondrial function. Results: Complex I and III dysfunction was induced in a cell model using the respiratory inhibitors rotenone and antimycin, resulting in mitochondrial dysfunction and enhanced ROS levels. Both treatments lead to elevated levels of Aβ. Presence of an antioxidant rescued mitochondrial function and reduced formation of Aβ, demonstrating that the observed effects depended on ROS. Conversely, cells overproducing Aβ showed impairment of mitochondrial function such as comprised mitochondrial respiration, strongly altered morphology, and reduced intracellular mobility of mitochondria. Again, the capability of these cells to generate Aβ was partly reduced by an antioxidant, indicating that Aβ formation was also ROS dependent. Moreover, mice with a genetic defect in complex I, or AD mice treated with a complex I inhibitor, showed enhanced Aβ levels in vivo. Innovation: We show for the first time that mitochondrion-derived ROS are sufficient to trigger Aβ production in vitro and in vivo. Conclusion: Several lines of evidence show that mitochondrion-derived ROS result in enhanced amyloidogenic amyloid precursor protein processing, and that Aβ itself leads to mitochondrial dysfunction and increased ROS levels. We propose that starting from mitochondrial dysfunction a vicious cycle is triggered that contributes to the pathogenesis of sporadic AD. © 2012, Mary Ann Liebert, Inc.

Muller M.,Goethe University Frankfurt | Muller M.,Frankfurt Institute for Molecular Life science | Reichert A.S.,Goethe University Frankfurt | Reichert A.S.,Frankfurt Institute for Molecular Life science
Biochemical Society Transactions | Year: 2011

Autophagy is a fundamental cellular process promoting survival under various environmental stress conditions. Selective types of autophagy have gained much interest recently as they are involved in specific quality control mechanisms removing, for example, aggregated proteins or dysfunctional mitochondria. This is considered to counteract the development of a number of neurodegenerative disorders and aging. Here we review the role of mitophagy and mitochondrial dynamics in ensuring quality control of mitochondria. In particular, we provide possible explanations why mitophagy in yeast, in contrast with the situation in mammals, was found to be independent of mitochondrial fission. We further discuss recent findings linking these processes to nutrient sensing pathways and the general stress response in yeast. In particular, we propose a model for how the stress response protein Whi2 and the Ras/PKA (protein kinase A) signalling pathway are possibly linked and thereby regulate mitophagy. ©The Authors Journal compilation ©2011 Biochemical Society.

Mendl N.,Ludwig Maximilians University of Munich | Occhipinti A.,Goethe University Frankfurt | Occhipinti A.,Frankfurt Institute for Molecular Life science | Muller M.,Goethe University Frankfurt | And 6 more authors.
Journal of Cell Science | Year: 2011

Dysfunctional mitochondria show a reduced capacity for fusion and, as mitochondrial fission is maintained, become spatially separated from the intact network. By that mechanism, dysfunctional mitochondria have been proposed to be targeted for selective degradation by mitophagy, thereby providing a quality control system for mitochondria. In yeast, conflicting results concerning the role of mitochondrial dynamics in mitophagy have been reported. Here, we investigate the effects on mitophagy of altering mitochondrial fission and fusion, using biochemical, as well as fluorescence-based, assays. Rapamycin-induced mitophagy was shown to depend upon the autophagy-related proteins Atg11, Atg20 and Atg24, confirming that a selective type of autophagy occurred. Both fragmentation of mitochondria and inhibition of oxidative phosphorylation were not sufficient to trigger mitophagy, and neither deletion of the fission factors Dnm1, Fis1, Mdv1 or Caf4 nor expression of dominant-negative variants of Dnm1 impaired mitophagy. The diminished mitophagy initially observed in a Δfis1 mutant was not due to the absence of Fis1 but rather due to a secondary mutation in WHI2, which encodes a factor reported to function in the general stress response and the Ras-protein kinase A (PKA) signaling pathway. We propose that, in yeast, mitochondrial fission is not a prerequisite for the selective degradation of mitochondria, and that mitophagy is linked to the general stress response and the Ras-PKA signaling pathway. © 2011. Published by The Company of Biologists Ltd.

Dikov D.,Goethe University Frankfurt | Dikov D.,Frankfurt Institute for Molecular Life science | Reichert A.S.,Goethe University Frankfurt | Reichert A.S.,Frankfurt Institute for Molecular Life science
EMBO Journal | Year: 2011

Mitochondria are remarkably dynamic organelles undergoing frequent fusion and fission events. Impairment thereof is linked to numerous neurodegenerative disorders and dysregulation of apoptosis. The principal players mediating mitochondrial fission are considered to be well known and largely conserved between yeast and mammals. However, how the essential fission factor Drp1 is recruited to mitochondria and how its activity is regulated are far more complex than previously assumed. According to a recent study (Otera et al, 2010), recruitment of Drp1 and mitochondrial fission can be exerted by Mff. Surprisingly, these processes do not appear to require Fis1, apparently contradicting several earlier reports on the role of Fis1. Two studies reported in EMBO Reports (Palmer et al, 2011) and in this issue of The EMBO Journal (Zhao et al, 2011) help to shed light on these unexpected findings. They identified two homologous vertebrate-specific negative regulators of Drp1-dependent fission termed: MIEF1/MiD51 and MiD49. They are able to recruit Drp1 to mitochondria but, importantly, rather than promoting fission, bind and inhibit Drp1. In a mutually exclusive manner, MIEF1/MiD51 can form a complex either with Drp1 or with Fis1. Thus, Fis1 may indirectly promote mitochondrial fission by its ability to sequester MIEF1/MiD51, preventing this novel factor from inhibiting mitochondrial fission. Future studies will have to decipher the complex interplay between these novel factors and how they regulate mitochondrial dynamics. © 2011 European Molecular Biology Organization | All Rights Reserved.

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