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Review
. 2022 Mar 29;145(1):45-63.
doi: 10.1093/brain/awab426.

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Melissa A E van de Wal  1 , Merel J W Adjobo-Hermans  2 , Jaap Keijer  3 , Tom J J Schirris  4 , Judith R Homberg  5 , Mariusz R Wieckowski  6 , Sander Grefte  3 , Evert M van Schothorst  3 , Clara van Karnebeek  1   7   8 , Albert Quintana  9 , Werner J H Koopman  1   3
Affiliations
Review

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Melissa A E van de Wal et al. Brain. .

Abstract

Mitochondria are small cellular constituents that generate cellular energy (ATP) by oxidative phosphorylation (OXPHOS). Dysfunction of these organelles is linked to a heterogeneous group of multisystemic disorders, including diabetes, cancer, ageing-related pathologies and rare mitochondrial diseases. With respect to the latter, mutations in subunit-encoding genes and assembly factors of the first OXPHOS complex (complex I) induce isolated complex I deficiency and Leigh syndrome. This syndrome is an early-onset, often fatal, encephalopathy with a variable clinical presentation and poor prognosis due to the lack of effective intervention strategies. Mutations in the nuclear DNA-encoded NDUFS4 gene, encoding the NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) of complex I, induce 'mitochondrial complex I deficiency, nuclear type 1' (MC1DN1) and Leigh syndrome in paediatric patients. A variety of (tissue-specific) Ndufs4 knockout mouse models were developed to study the Leigh syndrome pathomechanism and intervention testing. Here, we review and discuss the role of complex I and NDUFS4 mutations in human mitochondrial disease, and review how the analysis of Ndufs4 knockout mouse models has generated new insights into the MC1ND1/Leigh syndrome pathomechanism and its therapeutic targeting.

Keywords: Leigh syndrome; intervention; mouse model; pathomechanism.

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Figures

Figure 1
Figure 1
Structure of CI and location of NDUFS4 and other subunits. (A) Side view of the cryogenic-electronic microscopy structure of CI in Ovis aries heart at 3.90 Å resolution (PDB accession number: 5LNK; www.rcsb.org), highlighting the position of the NDUFS4 protein (red) relative to the NDUFAB1, NDUFV3-10, NDUFS6 and NDUFA12 subunits. The two copies (α and β) of the NDUFAB1/SDAP accessory subunit are indicated. Yellow spheres mark iron-sulphur clusters. Transmembrane helices are depicted in the MIM-embedded part. (B) Same as A but now highlighting the position of the NDUFS4 protein relative to the NDUFV1, NDUFS1, NDUFA9, NDUFS7 and NDUFA12 subunits. (C) Same as B, but now depicting a view from the top and back of CI. The molecular graphics in this figure were created using the PyMOL Molecular Graphics System v.2.0 (Schrödinger-LLC, Mannheim, Germany).
Figure 2
Figure 2
Sequence of the human and mouse NDUFS4 and pathogenic NDUFS4 mutations. (A) Human (Homo sapiens) NDUFS4 pre-protein sequence (O43181 from UniProt: www.uniprot.org). The MTS is highlighted in bold red. The two PKA consensus phosphorylation sites in the MTS and NDUFS4 protein are highlighted by boxes. The AQDQ sequence (highlighted in pink) is also indicated. (B) Same as panel A but now for the mouse (Mus musculus) NDUFS4 protein sequence (Q9CXZ1). In the whole-body Ndufs4 knockout animal (Ndufs4−/−-WB), the last part of the MTS and the first 17 amino acids of NDUFS4 (highlighted in blue) were deleted. (C) Alignment of the pre-protein sequences in A and B. The MTS is highlighted in bold and identical amino acids are in green. The mature human and mouse NDUFS4 proteins differ by only four amino acids (highlighted in grey), rendering them 97% identical. (D) Schematic structure of NDUFS4 (NM_002495.2) consisting of five exons (not drawn to scale). The currently known mutations are highlighted (Table 2).
Figure 3
Figure 3
Consequences of Ndufs4 knockout. (A) Ndufs4 knockout induces absence of the NDUFS4 subunit of CI, near complete absence of the NDUFA12 subunit and increased levels of the CI-attached NDUFAF2 assembly factor. This results in an unstable CI holocomplex that is present at lower levels in situ and therefore displays a lower activity in Ndufs4−/− mice. On isolation, the unstable CI complex loses its N-module, resulting in an inactive ∼800 kDa subcomplex on BN–PAGE gels. Adapted from Adjobo-Hermans et al. (B) Genetic dissection of clinical signs in Ndufs4−/−-WB mice. Vglut2-expressing glutamatergic neurons mediate most of the phenotype of Ndufs4−/−-WB mice, such as motor and respiratory alterations, while GABAergic neurons are involved in basal ganglia inflammation, development of epilepsy and hypothermia. Conditional alteration in either population leads to reduced lifespan and decreased body weight. Cer = cerebellum; GPe = external globus pallidus; IO = inferior olive; KO = knockout; OB = olfactory bulb; SNr = substantia nigra pars reticulata; VN = vestibular nuclei; WT = wild-type. Adapted from Bolea et al.
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