Ndufs4 knockout mouse models of Leigh syndrome : pathophysiology and intervention
van de Wal, Melissa A. E. (Amalia Children's Hospital)
Adjobo-Hermans, Merel J. W. (Radboud Institute for Molecular Life Sciences (Holanda))
Keijer, Jaap (Wageningen University)
Schirris, Tom J. J. (Radboud Institute for Molecular Life Sciences (Holanda))
Homberg, Judith R. (Donders Institute for Brain)
Wieckowski, Mariusz R. (Nencki Institute of Experimental Biology)
Grefte, Sander (Wageningen University)
van Schothorst, Evert M. (Wageningen University)
van Karnebeek, Clara (Emma Children's Hospital)
Quintana Romero, Albert (Universitat Autònoma de Barcelona. Institut de Neurociències)
Koopman, Werner J. H. (Wageningen University)

Data:	2021
Resum:	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. The NDUFS4 gene encodes an accessory subunit of OXPHOS complex I and its mutation causes mitochondrial disease in children. Van de Wal et al. review how Ndufs4 knockout mouse models have provided new insights into the disease pathomechanism and potential intervention strategies for these disorders.
Ajuts:	European Commission 638106 Agencia Estatal de Investigación SAF2017-88108-R "la Caixa" Foundation 100010434 "la Caixa" Foundation LCF/PR/HR20/52400018
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Leigh syndrome ; Mouse model ; Pathomechanism ; Intervention
Publicat a:	Brain, Vol. 145 (november 2021) , p. 45-63, ISSN 1460-2156

DOI: 10.1093/brain/awab426
PMID: 34849584

19 p, 1.8 MB

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