A three-dimensional topology of complex I inferred from evolutionary correlations

Kensche, Philip; Duarte, Isabel Margarida; Huynen, Martijn A.

doi:10.1186/1472-6807-12-19

Cited by 10 publications

(11 citation statements)

References 97 publications

(144 reference statements)

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“…However, in Y. lipolytica mitochondria we found a marked reduction of complex I content suggesting that assembly efficiency was decreased. We found that N7BM and N7BML were never present together in any complex I (sub)assembly, strongly supporting the idea that the subunit N7BM replaces its paralog the assembly factor N7BML during complex I biogenesis (24). In any case, detachment of N7BML from the assembly intermediate required the presence of complex I subunits N7BM and NUMM in line with results recently obtained for N. crassa, where binding of the N7BML ortholog 13.4L to nascent complex I was shown immunologically (23).…”

Section: Discussionsupporting

confidence: 78%

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Accessory NUMM (NDUFS6) subunit harbors a Zn-binding site and is essential for biogenesis of mitochondrial complex I

Kmita

Wirth

Warnau

et al. 2015

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

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Mitochondrial proton-pumping NADH:ubiquinone oxidoreductase (respiratory complex I) comprises more than 40 polypeptides and contains eight canonical FeS clusters. The integration of subunits and insertion of cofactors into the nascent complex is a complicated multistep process that is aided by assembly factors. We show that the accessory NUMM subunit of complex I (human NDUFS6) harbors a Zn-binding site and resolve its position by X-ray crystallography. Chromosomal deletion of the NUMM gene or mutation of Zn-binding residues blocked a late step of complex I assembly. An accumulating assembly intermediate lacked accessory subunit N7BM (NDUFA12), whereas a paralog of this subunit, the assembly factor N7BML (NDUFAF2), was found firmly bound instead. EPR spectroscopic analysis and metal content determination after chromatographic purification of the assembly intermediate showed that NUMM is required for insertion or stabilization of FeS cluster N4.assembly | metal protein | FeS cluster | NDUFAF2 | NDUFA12 P roton-pumping NADH:ubiquinone oxidoreductase (respiratory complex I) is a multisubunit membrane protein complex with a central function in aerobic energy metabolism (1, 2). Fourteen central subunits that harbor the bioenergetic core functions are conserved from bacteria to humans. In addition, eukaryotic complex I comprises around 30 accessory subunits of largely unknown function. The structures of bacterial and mitochondrial complex I were analyzed by X-ray crystallography and electron microscopy (3-6). The central subunits can be assigned to functional modules for NADH oxidation (N-module), ubiquinone reduction (Q-module), and proton pumping (P-module). The subunits forming the N-and Q-module harbor a chain of FeS clusters that connects the NADH oxidation site with the ubiquinone reduction site where the redox energy is released to drive proton translocation.The assembly of complex I subunits is a multistep process that proceeds via defined intermediates and is aided by a number of assembly factors (7). It also requires the concerted insertion of preformed FeS clusters into several subunits of the N-and Q-module (8). Dysfunction of complex I is the most frequent cause of mitochondrial disorders (9). Pathogenic mutations were identified not only in central subunits, encoded by either nuclear or mitochondrial DNA, but also in accessory subunits and assembly factors. The aerobic yeast Yarrowia lipolytica has been established as a yeast genetic model system to study structure and function of eukaryotic complex I, as well as complex I linked diseases (10).In this study, we focused on the accessory subunit NUMM of Y. lipolytica complex I. NUMM belongs to a limited subset of accessory subunits that is already found in α-proteobacteria and harbors a conserved putative Zn-binding motif, comprising three cysteines and one histidine in its C-terminal part (11). Zn binding to complex I was previously reported for bovine complex I but its functional relevance and the position of the Zn site remained elusive (12, 13). A poly...

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Section: Discussionsupporting

confidence: 78%

“…Indeed, N7BM is also homologous to subunits NDUFA12, B17.2, and nuo13.4 from H. sapiens, B. taurus, and N. crassa, respectively ( Fig. S1D) that are paralogs of the respective assembly factors indicated above (22)(23)(24).…”

Section: Resultsmentioning

confidence: 98%

Accessory NUMM (NDUFS6) subunit harbors a Zn-binding site and is essential for biogenesis of mitochondrial complex I

Kmita

Wirth

Warnau

et al. 2015

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

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“…6 The exact role of NDUFA2 has yet to be defined, but proposed functions include complex I iron-sulfur cluster assembly and upkeep, and use of redox processes for assembly or regulation of enzymatic activity. 6,7 Only 1 patient has been previously described with a homozygous splice site mutation in NDUFA2 (c.208+5G>A) (MIM 602137) causing abnormal splicing of exon 2. This patient exhibited a clinical presentation of Leigh syndrome (MIM 256000).…”

Section: Introductionmentioning

confidence: 99%

Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy

et al. 2017

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Deficiencies of mitochondrial respiratory chain complex I frequently result in leukoencephalopathy in young patients, and different mutations in the genes encoding its subunits are still being uncovered. We report 2 patients with cystic leukoencephalopathy and complex I deficiency with recessive mutations in NDUFA2, an accessory subunit of complex I. The first patient was initially diagnosed with a primary systemic carnitine deficiency associated with a homozygous variant in SLC22A5, but also exhibited developmental regression and cystic leukoencephalopathy, and an additional diagnosis of complex I deficiency was suspected. Biochemical analysis confirmed a complex I deficiency, and whole-exome sequencing revealed a homozygous mutation in NDUFA2 (c.134A>C, p.Lys45Thr). Review of a biorepository of patients with unsolved genetic leukoencephalopathies who underwent whole-exome or genome sequencing allowed us to identify a second patient with compound heterozygous mutations in NDUFA2 (c.134A>C, p.Lys45Thr; c.225del, p.Asn76Metfs*4). Only 1 other patient with mutations in NDUFA2 and a different phenotype (Leigh syndrome) has previously been reported. This is the first report of cystic leukoencephalopathy caused by mutations in NDUFA2.

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“…Its 14 core subunits are evolutionarily conserved in bacteria and eukaryotes (1), with over 20 additional subunits in higher organisms (6). The hydrophilic domain provides an electron transfer chain from NADH via a flavine mononucleotide and eight to nine iron-sulfur centers to Q, located at the end of this chain (Fig.…”

mentioning

confidence: 99%

Electrostatics, hydration, and proton transfer dynamics in the membrane domain of respiratory complex I

Kaila

Wikström

Hummer

2014

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

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Complex I serves as the primary electron entry point into the mitochondrial and bacterial respiratory chains. It catalyzes the reduction of quinones by electron transfer from NADH, and couples this exergonic reaction to the translocation of protons against an electrochemical proton gradient. The membrane domain of the enzyme extends ∼180 Å from the site of quinone reduction to the most distant proton pathway. To elucidate possible mechanisms of the long-range proton-coupled electron transfer process, we perform large-scale atomistic molecular dynamics simulations of the membrane domain of complex I from Escherichia coli. We observe spontaneous hydration of a putative proton entry channel at the NuoN/K interface, which is sensitive to the protonation state of buried glutamic acid residues. In hybrid quantum mechanics/classical mechanics simulations, we find that the observed water wires support rapid proton transfer from the protein surface to the center of the membrane domain. To explore the functional relevance of the pseudosymmetric inverted-repeat structures of the antiporter-like subunits NuoL/M/N, we constructed a symmetry-related structure of a possible alternateaccess state. In molecular dynamics simulations, we find the resulting structural changes to be metastable and reversible at the protein backbone level. However, the increased hydration induced by the conformational change persists, with water molecules establishing enhanced lateral connectivity and pathways for proton transfer between conserved ionizable residues along the center of the membrane domain. Overall, the observed watergated transitions establish conduits for the unidirectional proton translocation processes, and provide a possible coupling mechanism for the energy transduction in complex I.biological energy conversion | proton pumping | Grotthuss mechanism |

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A three-dimensional topology of complex I inferred from evolutionary correlations

Cited by 10 publications

References 97 publications

Accessory NUMM (NDUFS6) subunit harbors a Zn-binding site and is essential for biogenesis of mitochondrial complex I

Accessory NUMM (NDUFS6) subunit harbors a Zn-binding site and is essential for biogenesis of mitochondrial complex I

Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy

Electrostatics, hydration, and proton transfer dynamics in the membrane domain of respiratory complex I

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