Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Melissa A.E. Van De Wal, Merel J.W. Adjobo-Hermans, Jaap Keijer, Tom J.J. Schirris, Judith R. Homberg, Mariusz R. Wieckowski, Sander Grefte, Evert M. Van Schothorst, Clara Van Karnebeek, Albert Quintana, Werner J.H. Koopman*

*Autor corresponent d’aquest treball

Producció científica: Contribució a una revistaArticle de revisióRecercaAvaluat per experts

29 Citacions (Web of Science)


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.

Idioma originalEnglish
Pàgines (de-a)45-63
Nombre de pàgines19
Estat de la publicacióPublicada - 1 de gen. 2022


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