@article{7395,
  abstract     = {The mitochondrial electron transport chain complexes are organized into supercomplexes (SCs) of defined stoichiometry, which have been proposed to regulate electron flux via substrate channeling. We demonstrate that CoQ trapping in the isolated SC I+III2 limits complex (C)I turnover, arguing against channeling. The SC structure, resolved at up to 3.8 Å in four distinct states, suggests that CoQ oxidation may be rate limiting because of unequal access of CoQ to the active sites of CIII2. CI shows a transition between “closed” and “open” conformations, accompanied by the striking rotation of a key transmembrane helix. Furthermore, the state of CI affects the conformational flexibility within CIII2, demonstrating crosstalk between the enzymes. CoQ was identified at only three of the four binding sites in CIII2, suggesting that interaction with CI disrupts CIII2 symmetry in a functionally relevant manner. Together, these observations indicate a more nuanced functional role for the SCs.},
  author       = {Letts, James A and Fiedorczuk, Karol and Degliesposti, Gianluca and Skehel, Mark and Sazanov, Leonid A},
  issn         = {1097-2765},
  journal      = {Molecular Cell},
  number       = {6},
  pages        = {1131--1146.e6},
  publisher    = {Cell Press},
  title        = {{Structures of respiratory supercomplex I+III2 reveal functional and conformational crosstalk}},
  doi          = {10.1016/j.molcel.2019.07.022},
  volume       = {75},
  year         = {2019},
}

@article{466,
  abstract     = {We consider Markov decision processes (MDPs) with multiple limit-average (or mean-payoff) objectives. There exist two different views: (i) the expectation semantics, where the goal is to optimize the expected mean-payoff objective, and (ii) the satisfaction semantics, where the goal is to maximize the probability of runs such that the mean-payoff value stays above a given vector. We consider optimization with respect to both objectives at once, thus unifying the existing semantics. Precisely, the goal is to optimize the expectation while ensuring the satisfaction constraint. Our problem captures the notion of optimization with respect to strategies that are risk-averse (i.e., ensure certain probabilistic guarantee). Our main results are as follows: First, we present algorithms for the decision problems which are always polynomial in the size of the MDP. We also show that an approximation of the Pareto-curve can be computed in time polynomial in the size of the MDP, and the approximation factor, but exponential in the number of dimensions. Second, we present a complete characterization of the strategy complexity (in terms of memory bounds and randomization) required to solve our problem. },
  author       = {Chatterjee, Krishnendu and Křetínská, Zuzana and Kretinsky, Jan},
  issn         = {1860-5974},
  journal      = {Logical Methods in Computer Science},
  number       = {2},
  publisher    = {International Federation of Computational Logic},
  title        = {{Unifying two views on multiple mean-payoff objectives in Markov decision processes}},
  doi          = {10.23638/LMCS-13(2:15)2017},
  volume       = {13},
  year         = {2017},
}

@article{515,
  abstract     = {The oxidative phosphorylation electron transport chain (OXPHOS-ETC) of the inner mitochondrial membrane is composed of five large protein complexes, named CI-CV. These complexes convert energy from the food we eat into ATP, a small molecule used to power a multitude of essential reactions throughout the cell. OXPHOS-ETC complexes are organized into supercomplexes (SCs) of defined stoichiometry: CI forms a supercomplex with CIII2 and CIV (SC I+III2+IV, known as the respirasome), as well as with CIII2 alone (SC I+III2). CIII2 forms a supercomplex with CIV (SC III2+IV) and CV forms dimers (CV2). Recent cryo-EM studies have revealed the structures of SC I+III2+IV and SC I+III2. Furthermore, recent work has shed light on the assembly and function of the SCs. Here we review and compare these recent studies and discuss how they have advanced our understanding of mitochondrial electron transport.},
  author       = {Letts, James A and Sazanov, Leonid A},
  issn         = {1545-9993},
  journal      = {Nature Structural and Molecular Biology},
  number       = {10},
  pages        = {800 -- 808},
  publisher    = {Nature Publishing Group},
  title        = {{Clarifying the supercomplex: The higher-order organization of the mitochondrial electron transport chain}},
  doi          = {10.1038/nsmb.3460},
  volume       = {24},
  year         = {2017},
}

@article{568,
  abstract     = {We study robust properties of zero sets of continuous maps f: X → ℝn. Formally, we analyze the family Z< r(f) := (g-1(0): ||g - f|| < r) of all zero sets of all continuous maps g closer to f than r in the max-norm. All of these sets are outside A := (x: |f(x)| ≥ r) and we claim that Z< r(f) is fully determined by A and an element of a certain cohomotopy group which (by a recent result) is computable whenever the dimension of X is at most 2n - 3. By considering all r > 0 simultaneously, the pointed cohomotopy groups form a persistence module-a structure leading to persistence diagrams as in the case of persistent homology or well groups. Eventually, we get a descriptor of persistent robust properties of zero sets that has better descriptive power (Theorem A) and better computability status (Theorem B) than the established well diagrams. Moreover, if we endow every point of each zero set with gradients of the perturbation, the robust description of the zero sets by elements of cohomotopy groups is in some sense the best possible (Theorem C).},
  author       = {Franek, Peter and Krcál, Marek},
  issn         = {1532-0073},
  journal      = {Homology, Homotopy and Applications},
  number       = {2},
  pages        = {313 -- 342},
  publisher    = {International Press},
  title        = {{Persistence of zero sets}},
  doi          = {10.4310/HHA.2017.v19.n2.a16},
  volume       = {19},
  year         = {2017},
}

@article{1209,
  abstract     = {NADH-ubiquinone oxidoreductase (complex I) is the largest (∼1 MDa) and the least characterized complex of the mitochondrial electron transport chain. Because of the ease of sample availability, previous work has focused almost exclusively on bovine complex I. However, only medium resolution structural analyses of this complex have been reported. Working with other mammalian complex I homologues is a potential approach for overcoming these limitations. Due to the inherent difficulty of expressing large membrane protein complexes, screening of complex I homologues is limited to large mammals reared for human consumption. The high sequence identity among these available sources may preclude the benefits of screening. Here, we report the characterization of complex I purified from Ovis aries (ovine) heart mitochondria. All 44 unique subunits of the intact complex were identified by mass spectrometry. We identified differences in the subunit composition of subcomplexes of ovine complex I as compared with bovine, suggesting differential stability of inter-subunit interactions within the complex. Furthermore, the 42-kDa subunit, which is easily lost from the bovine enzyme, remains tightly bound to ovine complex I. Additionally, we developed a novel purification protocol for highly active and stable mitochondrial complex I using the branched-chain detergent lauryl maltose neopentyl glycol. Our data demonstrate that, although closely related, significant differences exist between the biochemical properties of complex I prepared from ovine and bovine mitochondria and that ovine complex I represents a suitable alternative target for further structural studies. },
  author       = {Letts, James A and Degliesposti, Gianluca and Fiedorczuk, Karol and Skehel, Mark and Sazanov, Leonid A},
  journal      = {Journal of Biological Chemistry},
  number       = {47},
  pages        = {24657 -- 24675},
  publisher    = {American Society for Biochemistry and Molecular Biology},
  title        = {{Purification of ovine respiratory complex i results in a highly active and stable preparation}},
  doi          = {10.1074/jbc.M116.735142},
  volume       = {291},
  year         = {2016},
}

@article{1226,
  abstract     = {Mitochondrial complex I (also known as NADH:ubiquinone oxidoreductase) contributes to cellular energy production by transferring electrons from NADH to ubiquinone coupled to proton translocation across the membrane. It is the largest protein assembly of the respiratory chain with a total mass of 970 kilodaltons. Here we present a nearly complete atomic structure of ovine (Ovis aries) mitochondrial complex I at 3.9 Å resolution, solved by cryo-electron microscopy with cross-linking and mass-spectrometry mapping experiments. All 14 conserved core subunits and 31 mitochondria-specific supernumerary subunits are resolved within the L-shaped molecule. The hydrophilic matrix arm comprises flavin mononucleotide and 8 iron-sulfur clusters involved in electron transfer, and the membrane arm contains 78 transmembrane helices, mostly contributed by antiporter-like subunits involved in proton translocation. Supernumerary subunits form an interlinked, stabilizing shell around the conserved core. Tightly bound lipids (including cardiolipins) further stabilize interactions between the hydrophobic subunits. Subunits with possible regulatory roles contain additional cofactors, NADPH and two phosphopantetheine molecules, which are shown to be involved in inter-subunit interactions. We observe two different conformations of the complex, which may be related to the conformationally driven coupling mechanism and to the active-deactive transition of the enzyme. Our structure provides insight into the mechanism, assembly, maturation and dysfunction of mitochondrial complex I, and allows detailed molecular analysis of disease-causing mutations.},
  author       = {Fiedorczuk, Karol and Letts, James A and Degliesposti, Gianluca and Kaszuba, Karol and Skehel, Mark and Sazanov, Leonid A},
  journal      = {Nature},
  number       = {7625},
  pages        = {406 -- 410},
  publisher    = {Nature Publishing Group},
  title        = {{Atomic structure of the entire mammalian mitochondrial complex i}},
  doi          = {10.1038/nature19794},
  volume       = {538},
  year         = {2016},
}