--- _id: '7788' abstract: - lang: eng text: Mutations in NDUFS4, which encodes an accessory subunit of mitochondrial oxidative phosphorylation (OXPHOS) complex I (CI), induce Leigh syndrome (LS). LS is a poorly understood pediatric disorder featuring brain-specific anomalies and early death. To study the LS pathomechanism, we here compared OXPHOS proteomes between various Ndufs4−/− mouse tissues. Ndufs4−/− animals displayed significantly lower CI subunit 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. article_number: '148213' article_processing_charge: No article_type: original author: - first_name: Merel J.W. full_name: Adjobo-Hermans, Merel J.W. last_name: Adjobo-Hermans - first_name: Ria full_name: De Haas, Ria last_name: De Haas - first_name: Peter H.G.M. full_name: Willems, Peter H.G.M. last_name: Willems - first_name: Aleksandra full_name: Wojtala, Aleksandra last_name: Wojtala - first_name: Sjenet E. full_name: Van Emst-De Vries, Sjenet E. last_name: Van Emst-De Vries - first_name: Jori A. full_name: Wagenaars, Jori A. last_name: Wagenaars - first_name: Mariel full_name: Van Den Brand, Mariel last_name: Van Den Brand - first_name: Richard J. full_name: Rodenburg, Richard J. last_name: Rodenburg - first_name: Jan A.M. full_name: Smeitink, Jan A.M. last_name: Smeitink - first_name: Leo G. full_name: Nijtmans, Leo G. last_name: Nijtmans - first_name: Leonid A full_name: Sazanov, Leonid A id: 338D39FE-F248-11E8-B48F-1D18A9856A87 last_name: Sazanov orcid: 0000-0002-0977-7989 - first_name: Mariusz R. full_name: Wieckowski, Mariusz R. last_name: Wieckowski - first_name: Werner J.H. full_name: Koopman, Werner J.H. last_name: Koopman citation: ama: 'Adjobo-Hermans MJW, De Haas R, Willems PHGM, et al. NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2. Biochimica et Biophysica Acta - Bioenergetics. 2020;1861(8). doi:10.1016/j.bbabio.2020.148213' apa: 'Adjobo-Hermans, M. J. W., De Haas, R., Willems, P. H. G. M., Wojtala, A., Van Emst-De Vries, S. E., Wagenaars, J. A., … Koopman, W. J. H. (2020). NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2. Biochimica et Biophysica Acta - Bioenergetics. Elsevier. https://doi.org/10.1016/j.bbabio.2020.148213' chicago: 'Adjobo-Hermans, Merel J.W., Ria De Haas, Peter H.G.M. Willems, Aleksandra Wojtala, Sjenet E. Van Emst-De Vries, Jori A. Wagenaars, Mariel Van Den Brand, et al. “NDUFS4 Deletion Triggers Loss of NDUFA12 in Ndufs4−/− Mice and Leigh Syndrome Patients: A Stabilizing Role for NDUFAF2.” Biochimica et Biophysica Acta - Bioenergetics. Elsevier, 2020. https://doi.org/10.1016/j.bbabio.2020.148213.' ieee: 'M. J. W. Adjobo-Hermans et al., “NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2,” Biochimica et Biophysica Acta - Bioenergetics, vol. 1861, no. 8. Elsevier, 2020.' ista: 'Adjobo-Hermans MJW, De Haas R, Willems PHGM, Wojtala A, Van Emst-De Vries SE, Wagenaars JA, Van Den Brand M, Rodenburg RJ, Smeitink JAM, Nijtmans LG, Sazanov LA, Wieckowski MR, Koopman WJH. 2020. NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2. Biochimica et Biophysica Acta - Bioenergetics. 1861(8), 148213.' mla: 'Adjobo-Hermans, Merel J. W., et al. “NDUFS4 Deletion Triggers Loss of NDUFA12 in Ndufs4−/− Mice and Leigh Syndrome Patients: A Stabilizing Role for NDUFAF2.” Biochimica et Biophysica Acta - Bioenergetics, vol. 1861, no. 8, 148213, Elsevier, 2020, doi:10.1016/j.bbabio.2020.148213.' short: M.J.W. Adjobo-Hermans, R. De Haas, P.H.G.M. Willems, A. Wojtala, S.E. Van Emst-De Vries, J.A. Wagenaars, M. Van Den Brand, R.J. Rodenburg, J.A.M. Smeitink, L.G. Nijtmans, L.A. Sazanov, M.R. Wieckowski, W.J.H. Koopman, Biochimica et Biophysica Acta - Bioenergetics 1861 (2020). date_created: 2020-05-03T22:00:47Z date_published: 2020-08-01T00:00:00Z date_updated: 2023-08-21T06:19:18Z day: '01' ddc: - '570' department: - _id: LeSa doi: 10.1016/j.bbabio.2020.148213 external_id: isi: - '000540842000012' pmid: - '32335026' file: - access_level: open_access checksum: a9b152381307cf45fe266a8dc5640388 content_type: application/pdf creator: dernst date_created: 2020-05-04T12:25:19Z date_updated: 2020-07-14T12:48:03Z file_id: '7798' file_name: 2020_BBA_Adjobo_Hermans.pdf file_size: 3826792 relation: main_file file_date_updated: 2020-07-14T12:48:03Z has_accepted_license: '1' intvolume: ' 1861' isi: 1 issue: '8' language: - iso: eng month: '08' oa: 1 oa_version: Published Version pmid: 1 publication: Biochimica et Biophysica Acta - Bioenergetics publication_identifier: eissn: - '18792650' issn: - '00052728' publication_status: published publisher: Elsevier quality_controlled: '1' scopus_import: '1' status: public title: 'NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2' tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 1861 year: '2020' ...