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Murphy M.P.,MRC Mitochondrial Biology Unit
Cell Metabolism | Year: 2013

Mitochondrial dysfunction is often associated with increased reactive oxygen species (ROS) production by the organelle itself. Leadsham et al. (2013) now show that the link between mitochondrial damage and ROS is more complicated, at least in yeast, where signals from damaged mitochondria increase ROS production from the endoplasmic reticulum surface. © 2013 Elsevier Inc. Source

Walker J.E.,MRC Mitochondrial Biology Unit
Biochemical Society Transactions | Year: 2013

The ATP synthases are multiprotein complexes found in the energy-transducing membranes of bacteria, chloroplasts and mitochondria. They employ a transmembrane protonmotive force, Ap, as a source of energy to drive a mechanical rotary mechanism that leads to the chemical synthesis of ATP from ADP and Pi. Their overall architecture, organization and mechanistic principles are mostly well established, but other features are less well understood. For example, ATP synthases from bacteria, mitochondria and chloroplasts differ in the mechanisms of regulation of their activity, and the molecular bases of these different mechanisms and their physiological roles are only just beginning to emerge. Another crucial feature lacking a molecular description is how rotation driven by Ap is generated, and how rotation transmits energy into the catalytic sites of the enzyme to produce the stepping action during rotation. One surprising and incompletely explained deduction based on the symmetries of c-rings in the rotor of the enzyme is that the amount of energy required by the ATP synthase to make an ATP molecule does not have a universal value. ATP synthases from multicellular organisms require the least energy, whereas the energy required to make an ATP molecule in unicellular organisms and chloroplasts is higher, and a range of values has been calculated. Finally, evidence is growing for other roles of ATP synthases in the inner membranes of mitochondria. Here the enzymes form supermolecular complexes, possibly with specific lipids, and these complexes probably contribute to, or even determine, the formation of the cristae. © 2013 Biochemical Society. Source

Murphy M.P.,MRC Mitochondrial Biology Unit
Antioxidants and Redox Signaling | Year: 2012

The mitochondrial matrix contains much of the machinery at the heart of metabolism. This compartment is also exposed to a high and continual flux of superoxide, hydrogen peroxide, and related reactive species. To protect mitochondria from these sources of oxidative damage, there is an integrated set of thiol systems within the matrix comprising the thioredoxin/peroxiredoxin/ methionine sulfoxide reductase pathways and the glutathione/glutathione peroxidase/glutathione-S-transferase/glutaredoxin pathways that in conjunction with protein thiols prevent much of this oxidative damage. In addition, the changes in the redox state of many components of these mitochondrial thiol systems may transduce and relay redox signals within and through the mitochondrial matrix to modulate the activity of biochemical processes. Recent Advances: Here, mitochondrial thiol systems are reviewed, and areas of uncertainty are pointed out, focusing on recent developments in our understanding of their roles. Critical Issues: The areas of particular focus are on the multiple, overlapping roles of mitochondrial thiols and on understanding how these thiols contribute to both antioxidant defenses and redox signaling. Future Directions: Recent technical progress in the identification and quantification of thiol modifications by redox proteomics means that many of the questions raised about the multiple roles of mitochondrial thiols can now be addressed. © 2012, Mary Ann Liebert, Inc. Source

Holt I.J.,MRC Mitochondrial Biology Unit
Trends in Genetics | Year: 2010

Because mitochondrial genes encode proteins essential for aerobic ATP production, mitochondrial DNA defects can cause an energy crisis. These defects fall into two broad categories: primary mutations in mitochondrial DNA and mutations in nuclear genes, whose protein products are involved in mitochondrial DNA maintenance. Evidence is accumulating that both types of defects can cause mitochondrial DNA loss. Hence, regulatory factors, which determine whether mitochondrial DNA molecules are maintained or lost, potentially play a more important role in these disorders than hitherto recognised. Candidates include reactive oxygen species (ROS) and the tumour suppressor p53. The cell might not always be the best judge of when to dispense with the services of mitochondrial DNA, and so interventions that favour its retention could potentially limit the adverse effects of pathological mitochondrial DNAs. © 2010 Elsevier Ltd. All rights reserved. Source

Vinothkumar K.R.,University of Cambridge | Zhu J.,MRC Mitochondrial Biology Unit | Hirst J.,MRC Mitochondrial Biology Unit
Nature | Year: 2014

Complex I (NADH:ubiquinone oxidoreductase) is essential for oxidative phosphorylation in mammalian mitochondria. It couples electron transfer from NADH to ubiquinone with proton translocation across the energy-transducing inner membrane, providing electrons for respiration and driving ATP synthesis. Mammalian complex I contains 44 different nuclear- and mitochondrial-encoded subunits, with a combined mass of 1 MDa. The 14 conserved 'core' subunits have been structurally defined in the minimal, bacterial complex, but the structures and arrangement of the 30 'supernumerary' subunits are unknown. Here we describe a 5 Å resolution structure of complex I from Bos taurus heart mitochondria, a close relative of the human enzyme, determined by single-particle electron cryo-microscopy. We present the structures of the mammalian core subunits that contain eight iron-sulphur clusters and 60 transmembrane helices, identify 18 supernumerary transmembrane helices, and assign and model 14 supernumerary subunits. Thus, we considerably advance knowledge of the structure of mammalian complex I and the architecture of its supernumerary ensemble around the core domains. Our structure provides insights into the roles of the supernumerary subunits in regulation, assembly and homeostasis, and a basis for understanding the effects of mutations that cause a diverse range of human diseases. ©2014 Macmillan Publishers Limited. All rights reserved. Source

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