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PDF Hosted at the Radboud Repository of the Radboud University Nijmegen PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. https://hdl.handle.net/2066/220251 Please be advised that this information was generated on 2021-09-27 and may be subject to change. BBA - Bioenergetics 1861 (2020) 148213 Contents lists available at ScienceDirect BBA - Bioenergetics journal homepage: www.elsevier.com/locate/bbabio NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh T syndrome patients: A stabilizing role for NDUFAF2 Merel J.W. Adjobo-Hermansa, Ria de Haasb, Peter H.G.M. Willemsa, Aleksandra Wojtalac, Sjenet E. van Emst-de Vriesa, Jori A. Wagenaarsa, Mariel van den Brandb, Richard J. Rodenburgb, ⁎ Jan A.M. Smeitinkb, Leo G. Nijtmansb,1, Leonid A. Sazanovd, Mariusz R. Wieckowskic, , ⁎⁎ Werner J.H. Koopmana, a Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud Center for Mitochondrial Medicine, Radboudumc, Nijmegen, the Netherlands b Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboudumc, Nijmegen, the Netherlands c Nencki Institute of Experimental Biology, Warsaw, Poland d Institute of Science and Technology, Klosterneuburg, Austria ARTICLE INFO ABSTRACT Keywords: Mutations in NDUFS4, which encodes an accessory subunit of mitochondrial oxidative phosphorylation NADH:ubiquinone oxidoreductase (OXPHOS) complex I (CI), induce Leigh syndrome (LS). LS is a poorly understood pediatric disorder featuring Leigh syndrome brain-specific anomalies and early death. To study the LS pathomechanism, we here compared OXPHOSpro- Proteomics teomes between various Ndufs4−/− mouse tissues. Ndufs4−/− animals displayed significantly lower CI subunit Fibroblasts levels in brain/diaphragm relative to other tissues (liver/heart/kidney/skeletal muscle), whereas other OXPHOS subunit levels were not reduced. Absence of NDUFS4 induced near complete absence of the NDUFA12 accessory subunit, a 50% reduction in other CI subunit levels, and an increase in specific CI assembly factors. Among the latter, NDUFAF2 was most highly increased. Regarding NDUFS4, NDUFA12 and NDUFAF2, identical results were obtained in Ndufs4−/− mouse embryonic fibroblasts (MEFs) and NDUFS4-mutated LS patient cells. Ndufs4−/− MEFs contained active CI in situ but blue-native-PAGE highlighted that NDUFAF2 attached to an inactive CI subcomplex (CI-830) and inactive assemblies of higher MW. In NDUFA12-mutated LS patient cells, NDUFA12 absence did not reduce NDUFS4 levels but triggered NDUFAF2 association to active CI. BN-PAGE revealed no such association in LS patient fibroblasts with mutations in other CI subunit-encoding genes where NDUFAF2 was attached to CI-830 (NDUFS1, NDUFV1 mutation) or not detected (NDUFS7 mutation). Supported by enzymological and CI in silico structural analysis, we conclude that absence of NDUFS4 induces near complete absence of NDUFA12 but not vice versa, and that NDUFAF2 stabilizes active CI in Ndufs4−/− mice and LS patient cells, perhaps in concert with mitochondrial inner membrane lipids. 1. Introduction multi-subunit complexes (CII-CV; [1]). CI transfers electrons from NADH to ubiquinone and uses the energy released by this process to Mitochondrial complex I (CI or NADH:ubiquinone oxidoreductase; convey protons (H+) from the mitochondrial matrix across the mi- EC 1.6.5.3) is the first and largest (~1 MDa) complex of the oxidative tochondrial inner membrane (MIM). This process contributes to estab- phosphorylation (OXPHOS) system, which further consists of four other lishment of a trans-MIM proton-motive force (PMF) that is used to Abbreviations: BN-PAGE, blue-native polyacrylamide gel electrophoresis; CI-V, complex I to V; CNS, Central Nervous System; KO, knockout; LS, Leigh Syndrome; MEFs, mouse embryonic fibroblasts; MIM, mitochondrial inner membrane; NDUFA12, NADH-ubiquinone oxidoreductase subunit A12; NDUFAF2, NADH-ubiquinone oxidoreductase complex assembly factor 2; NDUFS4, NADH-ubiquinone oxidoreductase Fe-S protein 4; OXPHOS, oxidative phosphorylation; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; WT, wild-type ⁎ Correspondence to: M.R. Wieckowski, Nencki Institute of Experimental Biology, Pasteur 3, Warsaw, Poland. ⁎⁎ Correspondence to: W.J.H. Koopman, Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Centre (Radboudumc), P.O. Box 9101, NL-6500 HB Nijmegen, the Netherlands. E-mail addresses: [email protected] (M.R. Wieckowski), [email protected] (W.J.H. Koopman). 1 Deceased 1 May 2018. https://doi.org/10.1016/j.bbabio.2020.148213 Received 4 February 2020; Received in revised form 15 April 2020; Accepted 16 April 2020 Available online 23 April 2020 0005-2728/ © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/). M.J.W. Adjobo-Hermans, et al. BBA - Bioenergetics 1861 (2020) 148213 generate ATP by chemiosmotic coupling [2]. CI consists of three func- liver, heart, kidney, diaphragm, skeletal muscle) and analyzed LS pa- tional modules [3]: the N-module (NADH binding and oxidation), the tient cells harboring nDNA-encoded CI mutations (NDUFS1, NDUFS4, Q-module (electron transfer to ubiquinone) and the P-module (proton NDUFS7, NDUFV1, NDUFA12, NDUFAF2). We demonstrate that Ndufs4 pumping). Structurally, CI is L-shaped and consists of 45 subunits, one gene deletion reduces CI subunit levels and propose that NDUFAF2 and of which (NDUFAB1) occurs twice in the fully assembled complex [4,5]. possibly MIM lipids can stabilize active CI at the cellular level. For its catalytic activity CI requires 14 core proteins [6], half of which is encoded by the mitochondrial DNA (mtDNA: MTND1, MTND2, 2. Materials and methods MTND3, MTND4, MTND4L, MTND5, MTND6) and the remainder by the nuclear DNA (nDNA: NDUFV1, NDUFV2, NDUFS1, NDUFS2, NDUFS3, 2.1. Animal breeding, tissue dissection and proteomics analysis NDUFS7, NDUFS8). In addition to this catalytic core, CI contains 30 currently-identified nDNA-encoded accessory subunits of largely un- Initial breeding pairs of heterozygous Ndufs4+/− mice [31] were known function [7]. Biogenesis of CI is assisted by at least 14 nDNA- kindly donated by the Palmiter laboratory (Howard Hughes Medical encoded assembly factors and the current evidence suggests that its Institute, University of Washington, Seattle). Mice were group-housed assembly occurs by a mechanism in which five CI protein modules are at the Central Animal Facility (CDL) of the Radboud University at 22 °C pre-formed (N, Q/Pp-a, Pp-b, Pd-a and Pd-b) and subsequently com- with a day/night rhythm of 12 h. The animals had ad libitum access to bined [8]. The structural and functional architecture of CI was de- food and water and were fed on a standard animal diet (V1534-300 R/ scribed at various levels of detail in diverse biological models like the M-H; Ssniff GmbH, Soest, Germany). Ndufs4 whole-body knockout yeast Y. lipolytica, the eubacterium Thermus thermophilus, bovine heart, (Ndufs4−/−; KO) and wild-type (WT) mice were generated by crossing ovine heart and porcine heart [4,9–14]. At a higher level of organiza- heterozygote males and females as described previously [31,39]. The tion, CI forms a supramolecular assembly with CIII and CIV [15], the genotype of the mice was confirmed by polymerase chain reaction. structure and potential functional aspects of which were presented Animal experiments were approved by the Committee for Animal Ex- [13,16–19]. periments of the Radboud University Nijmegen Medical Center Nij- Mutations in CI structural subunits induce isolated CI deficiency megen, The Netherlands, in accordance with Dutch laws and regula- (OMIM 252010) and are primarily associated with Leigh syndrome (LS; tions and performed under the guidelines and regulations of the Dutch [20,21]). This syndrome is generally characterized by neurodegenera- Council for Animal Care. For proteomics analysis, three WT mice (2 tion, variable symptoms, mitochondrial dysfunction and bilateral CNS male, 1 female) and three KO (Ndufs4−/−) mice (2 male, 1 female) lesions [22]. The NDUFS4 gene encodes the 18-kDa NDUFS4 (NADH- were sacrificed 6 weeks after birth by decapitation. Different tissues ubiquinone oxidoreductase Fe-S protein 4) accessory subunit of CI, were isolated and extensively washed in PBS and stored in liquid ni- which plays an important role during CI assembly and in CI stability trogen. In case of the brain, a slice (1–1.5 mm thickness) was manually [23–27]. At the clinical level, NDUFS4 mutations primarily affect the dissected and contained parts of the following brain areas: cerebral brainstem, basal ganglia and (less frequently) the cerebral cortex and cortex, hippocampal formation, thalamus, hypothalamus, internal are typically associated with hypotonia, abnormal ocular movements, capsule, optic tract and the amygdala (Allen mouse brain atlas; http:// visual impairment, psychomotor arrest/regression and episodes of re- mouse.brain-map.org/). For comparison, other organs (from 1 KO and 1 spiratory failure [28]. On average, mutations in the NDUFS4 subunit WT animal; both males) were included in the proteomics analysis: liver, induce a 50% reduction of CI activity in patient fibroblasts and cause kidney, diaphragm, heart, and skeletal muscle from the hind leg (con- death within 10 months after birth [28]. taining: musculus vastus medialis,
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