---
_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. <i>Biochimica et Biophysica Acta - Bioenergetics</i>. 2020;1861(8).
    doi:<a href="https://doi.org/10.1016/j.bbabio.2020.148213">10.1016/j.bbabio.2020.148213</a>'
  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. <i>Biochimica et Biophysica Acta - Bioenergetics</i>.
    Elsevier. <a href="https://doi.org/10.1016/j.bbabio.2020.148213">https://doi.org/10.1016/j.bbabio.2020.148213</a>'
  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.” <i>Biochimica et Biophysica Acta -
    Bioenergetics</i>. Elsevier, 2020. <a href="https://doi.org/10.1016/j.bbabio.2020.148213">https://doi.org/10.1016/j.bbabio.2020.148213</a>.'
  ieee: 'M. J. W. Adjobo-Hermans <i>et al.</i>, “NDUFS4 deletion triggers loss of
    NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for
    NDUFAF2,” <i>Biochimica et Biophysica Acta - Bioenergetics</i>, 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.”
    <i>Biochimica et Biophysica Acta - Bioenergetics</i>, vol. 1861, no. 8, 148213,
    Elsevier, 2020, doi:<a href="https://doi.org/10.1016/j.bbabio.2020.148213">10.1016/j.bbabio.2020.148213</a>.'
  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'
...