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*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)


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.

Original languageEnglish
Pages (from-to)45-63
Number of pages19
Issue number1
Publication statusPublished - 1 Jan 2022


  • intervention
  • Leigh syndrome
  • mouse model
  • pathomechanism


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